E1608 Revised 4/11, Addendum #3
Eastern Cooperative Oncology Group
A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
STUDY CHAIR: F. Stephen Hodi, M.D. STUDY CO-CHAIR: David McDermott, M.D. STUDY STATISTICIAN: Sandra Lee, Sc.D. PATHOLOGY CO-CHAIR: Uma Rao, M.D. MELANOMA COMMITTEE CHAIR: John Kirkwood, M.D. Rev. 4/11 COMMUNITY CO-CHAIR: Gary Cohen, M.D.
Version Date: February 24, 2012
STUDY PARTICIPANTS ACTIVATION DATE ECOG US Sites Only December 28, 2010 CALGB Dana-Farber Cancer Institute Only PRE-ACTIVATION DATE November 1, 2010
Addendum #1 – Incorporated Prior to Activation Addendum #2 – 12/10 Addendum #3 – 4/11 Addendum #4 – 10/11 Addendum #5 – 4/12
Agents IND # NSC # Supply
Ipilimumab 10200 NSC 732442 NCI-Supplied
GM-CSF NSC 613795 Industry Supplied
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Table of Contents Schema...... i 1. Introduction ...... 1 2. Objectives ...... 11 3. Selection of Patients ...... 12 4. Registration and Randomization Procedures ...... 15 5. Treatment Plan...... 18 6. Measurement of Effect...... 33 7. Study Parameters ...... 44 8. Drug Formulation and Procurement...... 47 9. Statistical Considerations...... 55 10. Pathology Review ...... 57 11. Correlative Studies...... 59 12. Records to Be Kept...... 62 13. Patient Consent and Peer Judgment...... 62 14. References...... 62 Appendix I Informed Consent Template for Cancer Treatment Trials (English Language)...... 1 Appendix II Pathology Submission Guidelines ...... 1 Appendix III Patient Thank You Letter...... 1 Appendix IV Suggested Work-up and Treatment for IMMUNE-Related Adverse EVENTS (IRAEs) ...... 1 Appendix V Recommended Diarrhea Management Algorithm...... 1 Appendix VI Recommended Hepatotoxicity Management Algorithm...... 1 Appendix VII Recommended Endocrinopathy Management Algorithm ...... 1 Appendix VIII Shipping Kit Request Facsimile Form ...... 1 Appendix IX Specimen Shipment/Requisition Form...... 1 Appendix X Medication Diary...... 1 Appendix XI E1608 Cooperative Research and Development Agreement (CRADA)...... 1 Appendix XII E1608 GM-CSF Drug Request Form ...... 1 Appendix XIII Certificate of Destruction of Clinical Trial Drugs ...... 1 Appendix XIV Self-Administration Guide for GM-CSF...... 1 Rev. 4/12 Appendix XV Pre-Existing Autoimmune Diseases ...... 1
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STUDY CHAIR F. Stephen Hodi, M.D. Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Tel: (617) 632-5053 Fax: (617) 582-7992 Email: [email protected]
STUDY CHAIR LIAISON (SCL) Angie Tsiaras Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Tel: (617) 632-6460 Email: [email protected]
STUDY CO-CHAIR: David McDermott, M.D. Beth Israel Deaconess Medical Center 330 Brookline Avenue, KS-158 Boston, MA 02215 Tel: (617) 667-9920 Fax: (617) 667-9922 Email: [email protected]
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Schema
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1. Introduction
1.1 Research Hypothesis The combination of CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines demonstrates therapeutic synergies in multiple pre-clinical models (1). While CTLA-4 antibody blockade alone elicits minimal effects against poorly immunogenic tumors, concurrent vaccination with irradiated, GM-CSF secreting tumor cells is highly efficacious in the B16 melanoma, SM1 breast carcinoma, and TRAMP prostate carcinoma models. Cytotoxic T cells are critical for tumor destruction, but the augmented anti-cancer response may be associated with the loss of tolerance to normal differentiation antigens, culminating in autoimmune vitiligo (for melanoma) or prostatitis (for prostatic carcinoma). We have generated preliminary clinical data raising the possibility of important therapeutic interactions between CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines in patients. We initially administered a single dose of ipilimumab (3 mg/kg) to 7 previously vaccinated metastatic melanoma patients (2,3). While autoimmune toxicities were mild, ipilimumab stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in 3 of 3 metastatic melanoma patients previously vaccinated with irradiated, autologous GM-CSF secreting tumor cells, whereas ipilimumab did not elicit tumor necrosis in 4 of 4 metastatic melanoma patients previously immunized with defined melanosomal antigens. Pathologic analysis of the responding metastases resected following antibody infusion demonstrated CD4+ and CD8+ T cells, CD20+ B cells producing immunoglobulin, and granulocytes juxtaposed to dying melanoma cells; moreover, a striking circumferential lymphoid infiltrate was detected in occluded tumor blood vessels, resulting in extensive ischemic necrosis. To explore the interactions of CTLA-4 blockade and GM-CSF secreting tumor cells in more detail, we treated an additional 11 melanoma patients (2,3). In these studies, repetitive doses of ipilimumab (3 mg/kg) could be administered at two month intervals, beginning one month following the completion of vaccination. In this cohort, one complete response, two partial responses, and five prolonged stable disease were observed, all ongoing with a range of follow-up from 6 to 29 months. No patient manifested grade III or IV toxicity, although mild rashes and constitutional symptoms were noted. Consistent with pre-clinical studies indicating that CTLA-4 blockade stimulates Treg proliferation, we found CD4+FoxP3 expressing cells in the cutaneous inflammatory reactions and tumor metastases. To examine whether these principles were operative in other tumor types, we administered ipilimumab to 10 advanced ovarian carcinoma patients who were previously immunized with irradiated, autologous GM-CSF secreting tumor cells (2,3). In this cohort, 5 patients manifested a lupus-like rash and 2 showed inflammatory gastritis/colitis. Five patients displayed a reduction or stabilization of CA-125 levels (including one with a dramatic radiographic response) and one patient with normal CA-125 level showed extensive hemorrhagic tumor necrosis by pathologic analysis. ASCO presentations combining GM-CSF with CTLA-4 blockade in hormone refractory prostate cancer have demonstrated clinical responses, with > 50% experiencing declines in PSA. Correlative sciences demonstrated the expansion of both activated effector and regulatory cells in this patient population (4,5). Together, these findings suggest that more detailed analysis of the interplay of GM-CSF and CTLA-4 antibody blockade should be undertaken. One key issue with significant practical implications is whether the systemic administration of GM-CSF protein might synergize effectively with CTLA-4 blockade. In this context, the injection of recombinant GM-CSF protein can enhance dendritic cell activation and thereby potentiate anti-tumor T and B cell responses. The cytokine mediates anti-tumor effects in some patients with advanced prostate or ovarian carcinoma and is currently being evaluated as a vaccine adjuvant in Phase III trials in melanoma and lymphoma.
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There are increasing data that suggest the mechanism of action for immune modulatory agents such as CTLA-4 blockade results in differing clinical courses than those traditionally witnessed with traditional cytotoxic therapies (6). In some circumstances, the disease assessments may show increase in tumor burden and even new lesions before tumor regression which can be delayed. From these observations, a proposed response criteria (immune related response criteria or irRC) have been created in order to capture these clinical scenarios where patients may be receiving benefit to treatment but which are delayed by standard criteria. The sum of the products of diameters at tumor assessment using the irRC criteria for progressive disease incorporates the contribution of new measurable lesions. Each net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the size and growth kinetics of both old and new lesions as they appear. Immune Related Response Criteria (irRC) are outlined in Section 2.4.3. Mechanism of Action
Advances in the understanding of the mechanisms that regulate T cell activation have allowed the rational design of new strategies for immunotherapy of tumors, including melanoma. It has been known for some time that engagement of the T cell antigen receptor by itself is not sufficient for full T cell activation; a second co-stimulatory signal is required for induction of IL-2 production, proliferation and differentiation to effector function of naive T cells. Abundant data now indicate that the primary source of this costimulation is mediated by engagement of CD28 on the T cell surface by members of the B7 family on the antigen- presenting cell (APC) (7). (See Figure 1.) Expression of B7 has been shown to be limited to “professional” antigen presenting cells; that is, specialized cells of the hematopoietic lineage, including dendritic cells, activated macrophages, and activated B cells. It has been suggested that this sharply-defined restriction of B7 expression is a fail-safe mechanism for maintenance of peripheral T cell tolerance, insuring that T cell activation can only be stimulated by appropriate APCs (8). The fact that tumor cells do not express B7 contributes to their poor capacity to elicit immune responses (9,10). The demonstration that induction of expression of B7 on many tumor cells by transfection, transduction, or other mechanisms can heighten tumor immunogenicity led to great interest in pursuing this as an approach to tumor immunotherapy. As demonstrated in vivo in murine tumor models, the utility of B7 expression as a vaccination approach is limited by the following factors: (1) B7-expressing tumor cell vaccines are only effective when the tumor cells have a high degree of inherent immunogenicity; (2) while B7-expressing vaccines have been shown in many cases to be effective in inducing protective immune responses, they have demonstrated only limited utility in inducing responses to established tumors; and (3) inactivation of tumor cells by radiation has been shown to destroy the immuno-enhancing activity of the B7 gene product (11,12).
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In the past few years it has become apparent that co-stimulation is even more complex than originally thought. After activation, T cells express CTLA-4, a close homologue to CD28. CTLA-4 binds members of the B7 family with a much higher affinity than CD28 (13). Although there was initially some controversy as to the role of CTLA-4 in regulating T cell activation, it has become clear that CTLA-4 down-regulates T cell responses (14). This was initially suggested by the following in vitro observations: (1) blockade of CTLA-4/B7 interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4 with CD3 and CD28 inhibited T cell responses; and (3) administration of antibodies to CTLA-4 in vivo enhanced the immune response to peptide antigens or superantigens in mice (15,16,17,18). Blocking CTLA-4-B7 interaction while preserving signaling via CD28 resulted in enhanced T cell responses in vitro (16). Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came from examination of mice with a null mutation (19, 20, 21). CTLA-4 knockout mice appear to have spontaneously activated T cells evident at approximately 1 week after birth, followed by rampant lymphoproliferation and lymphadenopathy. These mice die at approximately 3 weeks of age, either as a result of polyclonal T cell expansion and tissue destruction or as a result of toxic shock resulting from lymphokine production by the T cells. Since thymocyte differentiation and selection proceed normally in CTLA-4-deficient mice, the rampant T cell expansion that occurs in the mice indicates that CTLA-4 plays a critical role in down- regulating T cell responses in the periphery (18). 1.2 Summary of Results of Investigational Program 1.2.1 Pharmacology of Ipilimumab Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody (mAb). In vitro studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity with human B7.1, B7.2 negative cell lines, and stains the appropriate cells without non-specific cross-reactivity in normal human tissues, as demonstrated by immunohistochemistry. Ipilimumab does cross-react with CTLA- 4 in non-human primates including cynomolgus monkeys. Ipilimumab was originally produced and purified from a hybridoma clone. Subsequently, a transfectoma (CHO cell) has been generated that is capable of producing more ipilimumab on a per cell basis than the hybridoma. Material from the transfectoma will be utilized in this and future ipilimumab clinical studies. Biochemical, immunologic and in vivo preclinical primate assessments demonstrated similarity between hybridoma and transfectoma-derived ipilimumab. 1.2.2 Pre-Clinical Toxicology of Ipilimumab Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab Investigator Brochure (IB). Non-clinical toxicity assessments included in vitro evaluation for the potential of ipilimumab to mediate complement-dependent cellular cytotoxicity (CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and toxicology assessments in cynomolgus monkeys alone and in the presence of vaccines. The in vitro studies demonstrated that ipilimumab did not mediate CDCC of PHA- or (CD)3-activated human T cells. However, low to moderate ADCC activity was noted at concentrations up to 50 ug/mL. These data are consistent with the requirement of high levels of antigen expression on the surface of target cells for efficient ADCC or CDCC. Since ipilimumab is a human IgG1, an isotype generally capable of mediating CDCC and ADCC, the lack of these activities is likely due to a very low expression of CTLA-4 on activated T cells. Therefore, these data suggest that ipilimumab treatment would not result in depletion of activated T cells in- vivo. Indeed, no depletion of T cells or T cell subsets were noted in toxicology studies in cynomolgus monkeys.
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No mortality or signs of toxicity were observed in three independent 14-day intravenous toxicology studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose. Furthermore, ipilimumab was evaluated in sub chronic and chronic toxicology studies in cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine and Melanoma Vaccine. Ipilimumab was well tolerated alone or in combination in all studies. There were no significant changes in clinical signs, body weight values, clinical pathology values or T cell activation markers. In addition, there were no significant histopathology changes in the stomach or colon. 1.2.3 Human Pharmacokinetics of Ipilimumab Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. The primary objective of Protocol MDX010-015 was to determine the safety and PK profile of single and multiple doses of ipilimumab derived from a transfectoma or hybridoma cell line. Mean plasma concentrations of ipilimumab administered at doses of 3 mg/kg (hybridoma-derived drug product); 2.8 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg (transfectoma-derived drug product) demonstrated approximate dose proportionality. Equimolar doses of hybridoma- derived and transfectoma-derived drug product had comparable PK profiles. The range of mean volume of distribution at steady state (Vss) across cohorts 2.8, 3, 5, 7.5, 10, 15, and 20 mg/kg, was 57.3 to 82.6 mL/kg, indicating drug distribution was mostly limited to the intravascular space. The clearance was low (range 0.11 to 0.29 mL/h/kg) and reflective of the half-life (range 297 to 414 h), which is consistent with the long terminal disposition phase of ipilimumab. There was moderate variability in the PK parameters among subjects, with CV of 11% to 48% in AUC (0-21d), 20% to 59% in CL, and 17% to 46% in Vss. 1.2.4 Clinical Safety with Ipilimumab Ipilimumab immunotherapy is currently under investigation in patients with unresectable advanced melanoma (unresectable Stage III or Stage IV) to potentially demonstrate an improvement in survival outcomes that represent a large unmet medical need in this population. Ipilimumab has been administered to approximately 2633 patients with different cancers in 24 completed or ongoing clinical trials as of March 31, 2008 with a dose range between 0.3 mg/kg and 20 mg/kg. Most experience with ipilimumab exists at the 3 mg/kg and 10 mg/kg dose levels. Patients who received ipilimumab at 3 mg/kg were treated in clinical studies conducted early in the development program and received either a single or multiple injections. Intra-patient dose escalation indicated that patients who were unresponsive at the 3 mg/kg dose level may have responded to 9 mg/kg. Based on preliminary data on the 10 mg/kg dose level of ipilimumab, the ongoing clinical program investigating ipilimumab in metastatic melanoma utilizes the 10 mg/kg dose level with the expectation that 10 mg/kg will prove more beneficial than 3 mg/kg. 1.2.4.1 Details of Drug-Related Adverse Events Drug-related adverse events (AEs) were reported in studies with ipilimumab as monotherapy as well as in combination studies with vaccines, cytokines or chemotherapy. The AE profile of ipilimumab is relatively well characterized, with most drug-related AEs being immune- related adverse events (IRAEs), which are considered to be associated with the mechanism of action of ipilimumab. The most common IRAEs are colitis and diarrhea, rash, pruritis, deficiencies of endocrine organs (pituitary, adrenal or thyroid), hepatitis, and uveitis. Rare complications are bowel perforations (~1%) resulting from underlying severe colitis, which have required surgical intervention.
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1.2.4.2 Drug-Related Serious Adverse Events Drug-related Grade 3 or Grade 4 serious adverse events (SAEs) include: rash/desquamation, pruritis, uveitis, speech impairment, abdominal pain, diarrhea/colitis, nausea/vomiting, transaminase elevation, adrenal insufficiency, panhypopituitarism and atrial fibrillation. Some of these events, such as rash/desquamation, pruritis, uveitis, diarrhea/colitis, transaminase elevation, adrenal insufficiency and panhypopituitarism, may represent drug induced IRAEs (see Appendix IV). Refer to the most recent version of the Ipilimumab Investigator Brochure for the latest update on SAEs. Among subjects treated with ipilimumab 10 mg/kg, SAEs considered possibly, probably, or definitely related to study drug were reported for 26% of subjects (176/675). Drug related SAEs reported in at least 1% of the 675 subjects at 10 mg/kg included diarrhea (10%), colitis (7%), vomiting (3%), dehydration (3%), autoimmune hepatitis (2%), hypopituitarism (2%), nausea (2%), abdominal pain (2%), pyrexia (2%), aspartate aminotransferase increased (1%), alanine aminotransferase increased (1%), and fatigue (1%). 1.2.5 Immune-Related Adverse Events (IRAEs) with Ipilimumab Many of the adverse events considered related to ipilimumab may be immune in nature and presumably a consequence of the intrinsic biological activity of ipilimumab. An IRAE is defined as any adverse event associated with drug exposure and consistent with an immune-mediated event. Disease progression, infections and other etiologic causes are ruled out or deemed unlikely as contributing to the event. Supportive data, such as autoimmune serology tests or biopsies, are helpful but not necessary to deem an event an IRAE. Events of unclear etiology which were plausibly “immune-mediated” have been conservatively categorized as IRAEs even if serologic or histopathology data are absent. These IRAEs likely reflect a loss of tolerance to some self antigens or an unchecked immune response to gut or skin flora. Some breakthrough of immunity may be inseparably linked to the clinical antitumor activity of ipilimumab. Approximately 60% of subjects developed any grade IRAEs which involved predominately the gastrointestinal (GI) tract, endocrine glands, liver, or skin. Based on data from the safety database, the number of subjects with serious IRAEs was approximately 15% (401/2633), including 8.2% for serious GI IRAEs (diarrhea and/or colitis), 2.2% of serious endocrinopathy (primarily hypophysitis/hypopituitarism) and <1% of serious skin IRAEs. Bowel perforation was reported in approximately 1% of subjects. With few exceptions these IRAEs were clinically manageable and reversible with supportive care or corticosteroids. In responding patients, addition of corticosteroids does not appear to have a temporal relationship to change in objective tumor response. Additionally, as of February 2006, there has been observation from a National Cancer Institute (NCI) study of bowel wall perforation in some patients who were administered a high-dose IL-2 following treatment with ipilimumab. Of the 22 patients administered high-dose IL-2, three patients experienced bowel wall perforations. This is a higher rate than would be expected with high-dose IL-2 treatment alone. All three patients had metastatic melanoma and had previously received their last dose of ipilimumab > 77 days before the first dose of IL-2. Two of the patients had clinically significant ipilimumab-related diarrhea or colitis and the symptoms had completely resolved prior to IL-2 administration. One patient did not experience ipilimumab-related diarrhea. It is unknown whether this observation represents a true association or is mechanistically unrelated to prior ipilimumab exposure.
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1.2.5.1 Drug-Related Deaths Based on reports from the safety database as of June 30, 2008, there have been reports of death (approximately 1% [28/3000]), deemed by the investigator as possibly related to the administration of study drug. The most common cause of drug related deaths was GI perforation. Other causes included multiorgan failure, sepsis, hypotension, acidosis, and adult respiratory distress syndrome. For details on all drug-related deaths, refer to the current version of the Ipilimumab Investigator Brochure. 1.2.5.2 Safety of 10 mg/kg Multiple Doses Based on a review of the program-wide SAE data as previously reported, evidence had suggested that ipilimumab-associated irAEs were dose dependent in frequency, and higher irAE rates had been observed at 10 mg/kg than at lower doses of ipilimumab. Subsequently, this dose- dependent effect was further demonstrated in CA184-022 in which three dose levels of ipilimumab were studied, including 0.3 vs 3 vs 10 mg/kg. Table 1 summarizes the overall irAE frequencies by dose from CA184-022 based on safety data from the locked clinical database. Qualitatively, the safety profile of ipilimumab at 10 mg/kg remains consistent with the low-dose safety profile in that most of the drug-related SAEs are characteristic of immune-related toxicity, and most of the irAEs are reported in the GI, hepatic, and endocrine systems. However, the data presented in Table 1 suggest that the frequency of irAEs in association with 10 mg/kg of ipilimumab at multiple doses is higher compared with the irAE frequency reported for lower doses.
Table 1. Summary of Immune-Related AEs by Treatment Groups - Treated Subjects (CA184-022) Number of Subjects (%) Ipilimumab 0.3 mg/kg 3 mg/kg 10 mg/kg (N=72) (N=71) (N=71) Overall irAEs 26.4 64.8 70.4 Grade 3-4 0 7.0 25.4 GI irAEs 16.7 32.4 39.4 Grade 3-4 0 2.8 15.5 Hepatic irAEs 0 0 2.8 Grade 3-4 0 0 2.8 Endocrine irAEs 0 5.6 4.2 Grade 3-4 0 2.8 1.4 Skin irAEs 12.5 45.1 46.5 Grade 3-4 0 1.4 4.2
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1.2.5.3 Neuropathies Isolated cases of motor neuropathy of an autoimmune origin have been reported among patients treated with ipilimumab. Two cases have been diagnosed as Guillain-Barre syndrome (GBS), only one of which was considered study related. As of July 2, 2008, 15 cases of neuropathy SAEs have been reported. Of these, 13 were assessed as unrelated to study therapy because alternative etiologies, including brain metastases, spinal cord compression, or aterial thrombosis, were identified in almost every case. 1.2.6 Clinical Efficacy of Ipilimumab Treatment with ipilimumab has demonstrated clinically important and durable tumor responses in several malignancies including melanoma, prostate cancer, and renal cell carcinoma. The most extensively studied tumor type has been malignant melanoma. Based on preliminary results, ipilimumab is active in patients with advanced stage malignant melanoma. The objective responses observed with ipilimumab may be considered durable as they have occurred across a spectrum of doses and schedules. Based on a preliminary analysis for study MDX010-15 involving ipilimumab 10 mg/kg multiple doses, 34.8% of patients (N = 23) were progression-free at 6 months and about 17.4% were progression-free at 1 year. In comparison, for Study MDX010-08 involving ipilimumab 3 mg/kg multiple doses, 10.8% patients (N = 37) had progression-free survival at 6 months and 8.4% at 1 year. Ipilimumab has also been studied in combination with chemotherapy (dacarbazine), melanoma vaccines (gp100), and cytokines (IL-2). Further details on clinical results can be found in the current version of the Ipilimumab Investigator Brochure. 1.2.6.1 Relationship Between Response and Immune Breakthrough Events in Patients with Metastatic Melanoma Drug-related AEs of any grade considered to be immune-mediated in nature (irAEs) were reported for 54.0% of subjects in clinical studies of ipilimumab. These irAEs are a consequence of inhibiting CTLA-4 function and most were reported as Grade 1 or 2. An association between BORR and higher grade (Grade 3-4) irAEs was suggested in early studies of ipilimumab 3 mg/kg but this association was not observed in 4 Phase 2 studies of ipilimumab (CA184022, CA184008, CA184007 and CA184004). There were proportionally more subjects with irAEs of any grade who experienced response or stable disease than subjects without irAEs who experienced response or stable disease, but due to the small sample sizes, these observations were statistically inconclusive (22,23,24). 1.3 Overall Risk/Benefit Assessment Most results from the 3 primary efficacy studies of ipilimumab suggest that the 10 mg/kg dose is active and offers the best benefit to risk ratio based on a 27.1% to 35.1% rate of disease control and a favorable 1-year survival rate of 48.6% to 59.1% compared with that reported in the literature (25.5% to 35%) (25,26,27,28). Substantial reductions in total tumor burden, including widely disseminated disease in the skin, lung, and/or other visceral disease sites, were reported. More than half the responses were reported in subjects staged with M1b or M1c advanced melanoma disease, which is most resistant to approved therapies. The kinetics of ipilimumab resulted in known patterns of clinical activity (CR, PR and SD) as well as novel patterns, characterized by reductions in total tumor burden, including existing and new lesions, after initial tumor volume increase and/or after appearance of new lesions. In the pretreated population at 10 mg/kg in 2 of the 3 studies, disease control after initial tumor volume increase and/or new lesions was reported for 9.7%
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of subjects. Across all 3 studies, stable disease was often accompanied by clinically relevant reductions in tumor burden compared to baseline. All patterns of response, including SD, appeared to result in favorable survival, based on 1-year survival rates. Characteristic organ-specific inflammatory irAEs were reported with ipilimumab therapy, typically during induction therapy. IrAEs were mostly reversible within days to weeks following cessation of therapy or treatment with symptomatic therapy, corticosteroids or other anti-inflammatory agents, depending upon severity. Accumulated clinical experience resulted in detailed toxicity management guidelines (also termed algorithms), by use of which irAEs can be effectively managed, especially when irAEs are recognized early and subjects are treated in a timely fashion. This can minimize the occurrence of irAE complications, such as GI perforation/colectomy or hepatic failure. Treatment with ipilimumab resulted in clinical activity in pretreated and previously untreated subjects with advanced melanoma. Clinically relevant reductions in the tumor burden from baseline were reported, together with a preliminary evidence of improved overall survival compared with published survival rates. These findings, together with evidence of a safety profile that is manageable with careful monitoring and appropriate intervention for treatment of immune-related toxicities, suggest an acceptable benefit to risk ratio. The overall risk-benefit ratio for patients entering this protocol is therefore at least comparable to and possibly better than alternative options. 1.4 GM-CSF GM-CSF is a naturally produced cytokine which targets bone marrow progenitor cells to increase production of neutrophils, monocytes, eosinophils, and dendritic cells. GM-CSF also has the ability to mature multiple circulating immune effector cells. In vitro studies have demonstrated that GM-CSF enhances chemotaxis, phagocytosis, and oxidative metabolism of neutrophils, enhances macrophage tumoricidal activity, and stimulates cytokine production and MHC expression enhancing antigen presentation (7-12). GM-CSF is a key cytokine in dendritic cell maturation as well as in initiating T cell responses (13-16). Most clinical studies with GM-CSF have focused their objectives on the cytokine’s effects on hematopoiesis. Specifically, studies have focused on its use in recovery of neutrophils following bone marrow transplant and/or high-dose chemotherapy administration, and treatment for myelodysplastic syndrome, aplastic anemia, and AIDS (17-20). In animal models utilizing transplantable tumors, mice vaccinated with irradiated tumor cells engineered to secrete a wide array of cytokines and immunostimulatory molecules revealed that GM-CSF was the most potent of those tested at inducing protective immunity (21). The mode of activity in this vaccination schema involves improved antigen presentation via recruitment of dendritic cells and macrophages to vaccination sites of the tumor. Whole cell vaccination strategies in humans with both autologous tumors and established cell lines have been performed, utilizing vaccinia virus, retroviruses, and adenoviruses encoding GM- CSF to infect cells. GM-CSF has also been used as an immunostimulatory adjuvant in peptide based vaccination strategies. In addition to GM-CSF having been used in a variety of vaccination strategies, it has also been directly injected into cutaneous metastases from melanoma. These studies revealed partial regression of treated lesions which on biopsies had lymphocyte infiltration with CD4+ T cells, CD8+ T cells, and dendritic cells. The therapeutic use of systemic GM-CSF has been investigated in high-risk melanoma patients as adjuvant therapy in patients surgically rendered free from metastatic disease (22,23). In one study, 30 patients with stage III disease (> 4 positive nodes or > 3 cm nodal mass) or stage IV NED were treated with GM- CSF 125 mcg/m2/day, cycles consisting of 14 days of treatment followed by 14 days off. There was minimal toxicity. In six patients with stage IV disease that had achieved a complete response to chemotherapy and subsequently received GM-CSF, four patients remained NED after two years. In another study of stage IIB melanoma patients, 7 of 9
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patients were disease-free after 30-42 months while receiving 1 mcg/kg TIW for one year. GM-CSF has been combined with IL-2 in several studies to complement activity seen in biochemotherapy regimens for patients with metastatic melanoma. In patients with advanced prostate cancer, GM-CSF at a dose of 250 micrograms TIW SQ for up to six months has shown modest biologic activity with a prostate-specific antigen response (24). These studies suggest the anti-tumor biologic contribution of GM-CSF. 1.5 GM-CSF Plus Ipilimumab The combination of CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines demonstrates therapeutic synergies in multiple pre-clinical models (1). While CTLA-4 antibody blockade alone elicits minimal effects against poorly immunogenic tumors, concurrent vaccination with irradiated, GM-CSF secreting tumor cells is highly efficacious in the B16 melanoma, SM1 breast carcinoma, and TRAMP prostate carcinoma models. Cytotoxic T cells are critical for tumor destruction, but the augmented anti-cancer response may be associated with the loss of tolerance to normal differentiation antigens, culminating in autoimmune vitiligo or prostatitis. We have generated preliminary clinical data raising the possibility of important therapeutic interactions between CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines in patients. We initially administered a single dose of ipilimumab (3 mg/kg) to 7 previously vaccinated metastatic melanoma patients (2,3). While autoimmune toxicities were mild, ipilimumab stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in 3 of 3 metastatic melanoma patients previously vaccinated with irradiated, autologous GM-CSF secreting tumor cells, whereas ipilimumab did not elicit tumor necrosis in 4 of 4 metastatic melanoma patients previously immunized with defined melanosomal antigens. Pathologic analysis of the responding metastases resected following antibody infusion demonstrated CD4+ and CD8+ T cells, CD20+ B cells producing immunoglobulin, and granulocytes juxtaposed to dying melanoma cells; moreover, a striking circumferential lymphoid infiltrate was detected in occluded tumor blood vessels, resulting in extensive ischemic necrosis. To explore the interactions of CTLA-4 blockade and GM-CSF secreting tumor cells in more detail, we treated an additional 11 melanoma patients (2,3). In these studies, repetitive doses of ipilimumab (3 mg/kg) could be administered at two month intervals, beginning one month following the completion of vaccination. In this cohort, one complete response, two partial responses, and five prolonged stable disease were observed, all ongoing with a range of follow-up from 6 to 29 months. No patient manifested grade III or IV toxicity, although mild rashes and constitutional symptoms were noted. Consistent with pre-clinical studies indicating that CTLA-4 blockade stimulates Treg proliferation, we found CD4+FoxP3 expressing cells in the cutaneous inflammatory reactions and tumor metastases. To examine whether these principles were operative in other tumor types, we administered ipilimumab to 10 advanced ovarian carcinoma patients who were previously immunized with irradiated, autologous GM-CSF secreting tumor cells (2,3). In this cohort, 5 patients manifested a lupus-like rash and 2 showed inflammatory gastritis/colitis. Five patients displayed a reduction or stabilization of CA-125 levels (including one with a dramatic radiographic response) and one patient with normal CA-125 level showed extensive hemorrhagic tumor necrosis by pathologic analysis. Recent ASCO presentations combining GM-CSF with CTLA-4 blockade in hormone refractory prostate cancer have demonstrated clinical responses, with > 50% experiencing declines in PSA. Correlative sciences demonstrated the expansion of both activated effector and regulatory cells in this patient population (4,5).
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1.6 Rationale for Current Study Together, the findings in preclinical animal models, clinical investigation of CTLA-4 blockade with whole cell GM-CSF secreting vaccines, and clinical experience of systemic GM-CSF plus ipilimumab in hormone refractory prostate cancer suggest that more detailed analysis of the interplay of GM-CSF and CTLA-4 antibody blockade should be undertaken. One key issue with significant practical implications is whether the systemic administration of GM- CSF protein might synergize effectively with CTLA-4 blockade. In this context, the injection of recombinant GM-CSF protein can enhance dendritic cell activation and thereby potentiate anti-tumor T and B cell responses. The cytokine mediates anti-tumor effects in some patients with advanced prostate or ovarian carcinoma and is currently being evaluated as a vaccine adjuvant in Phase III trials in melanoma and lymphoma.
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2. Objectives
2.1 Primary Objective To evaluate the overall survival for the combination of GM-CSF plus ipilimumab and ipilimumab alone in patients with advanced melanoma. 2.2 Secondary Objectives 2.2.1 To evaluate the progression-free survival, response rate, safety and tolerability for the combination of GM-CSF plus ipilimumab and ipilimumab alone in patients with advanced melanoma. 2.2.2 To explore the utility of immune related response criteria (irRC) prospectively in patients receiving ipilimumab.
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3. Selection of Patients Each of the criteria in the checklist that follows must be met in order for a patient to be considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist must be photocopied, completed and maintained in the patient’s chart. In calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered Day 28.
ECOG Patient No.
Patient’s Initials (L, F, M)
Physician Signature and Date
NOTE: All questions regarding eligibility should be directed to the study chair or study chair liaison. NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, signed, and dated prior to registration/randomization by the treating physician. Rev. 12/10 ______3.1 All sites of disease must be evaluated within 4 weeks prior to randomization. Patients must have measurable disease as defined by RECIST (see Section 6). ______3.2 No more than one prior systemic therapeutic regimen for unresectable stage III or stage IV melanoma. This includes chemotherapy, biologic therapy, biochemotherapy, or investigational treatment. This does not include any therapies given in the adjuvant setting. Rev. 4/11 ______3.3 Histologic diagnosis of metastatic melanoma. For unknown primary disease, diagnosis of metastatic disease by cytology FNA is not acceptable.
______3.4 Age ≥ 18 years. 3.5 Women must not be pregnant or breast-feeding due to unknown effects of ipilimumab and ______GM-CSF on the unborn fetus. All women of childbearing potential must have a blood test within 72 hours prior to randomization to rule out pregnancy. Female? ______(Yes or No) Date of blood test: ______Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be of childbearing potential. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.
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______3.6 Patients must have the following lab values obtained < 4 weeks prior to randomization ______3.6.1 WBC ≥ 2000/uL Date of test______Value______3.6.2 ANC≥ 1500/mcL Date of test______Value______3.6.3 Platelets ≥ 100,000/mcL Date of test______Value______3.6.4 Hemoglobin ≥ 8 g/dL Date of test______Value______3.6.5 Creatinine ≤ 3.0 x ULN Date of test______Value______ULN______3.6.6 AST and ALT < 2.5 x ULN AST______Date of test ______ULN______ALT______Date of test ______ULN______3.6.7 Bilirubin ≤ 3.0 x ULN, (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL) Date of test______Value______ULN______Gilbert’s Syndrome______
______3.7 No Concomitant therapy with any of the following: IL 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; must have been discontinued > 4 weeks. ______3.8 No infection with HIV. Due to the mechanism of action of ipilimumab and GM-CSF, activity and side effects in an immune compromised patient are unknown. ______3.9 No active infection with Hepatitis B. ______3.10 No active or chronic infection with Hepatitis C. ______3.11 ECOG performance status 0 or 1.
______3.12 Patients with any history of CNS metastases are excluded. ______3.13 Patients are excluded if they have a history of any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix. Rev. 4/12 ______3.14 Patients are excluded if they have a history of any autoimmune disease listed in Appendix XV. Patients with a history of autoimmune thyroiditis are eligible if their current thyroid disorder is treated and stable with replacement or other medical therapy.
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______3.15 Patients are excluded for any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
______3.16 Patients are excluded for receiving any non-oncology vaccine therapy used for prevention of infectious diseases for up to four weeks (28 days) prior to or after any dose of ipilimumab. ______3.17 Patients are excluded if they have a history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or agonist. ______3.18 Any concurrent medical condition requiring the use of systemic steroids is not permitted (the use of inhaled or topical steroids is permitted).
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4. Registration and Randomization Procedures
Submitting Regulatory Documents
Before an ECOG Institution may enter patients, protocol specific regulatory documents must be submitted to the CTSU Regulatory Office at the following address:
CTSU Regulatory Office Coalition of National Cancer Cooperative Groups 1818 Market Street, Suite 1100 Philadelphia, PA 19103 FAX: (215) 569-0206 Required Protocol Specific Regulatory Documents 1. CTSU Regulatory Transmittal Form 2. Copy of IRB Informed Consent Document NOTE: Any deletion or substantive modification of information concerning risks or alternative procedures contained in the sample informed consent document must be justified in writing by the investigator and approved by the IRB. 3. A. CTSU IRB Certification Form or B. HHS OMB No. 0990-0263 or C. IRB Approval Letter NOTE: The above submissions must include the following details:
• Indicate all sites approved for the protocol under an assurance number. • OHRP assurance number of reviewing IRB • Full protocol title and number • Version Date • Type of review (full board vs. expedited) • Date of review • Signature of IRB official
Rev. 4/11 The CTSU encourages you to go to the following CTSU RSS webpage so that more information on RSS2.0 as well as the submission forms can be accessed. Log in to http://www.ctsu.org and click on the Regulatory tab to access the RSS webpage. If you have questions regarding regulatory document submission, please telephone the CTSU Help Desk at (888) 823-5923 or e-mail [email protected]. Monday through Friday, 9:00am - 6:00pm. Patients must not start protocol treatment prior to registration. Treatment should start within three to five working days after registration. Institutions may register eligible patients to this study via the ECOG webpage 24 hours a day, 7 days a week, using the Web-based Patient Registration Program (https://webreg.ecog.org). If you need assistance or have questions, please telephone the Central Randomization Desk at the ECOG Coordinating Center at (617) 632-2022, Monday through Friday 9:00am – 5:00pm Eastern Time. Please note that a password is required to use this program. The following information will be requested:
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4.1 Protocol Number 4.2 Investigator Identification 4.2.1 Institution and affiliate name 4.2.2 Investigator’s name 4.3 Patient Identification 4.3.1 Patient’s initials and chart number 4.3.2 Patient’s Social Security number 4.3.3 Patient demographics 4.3.3.1 Sex 4.3.3.2 Birth date (mm/yyyy) 4.3.3.3 Race 4.3.3.4 Ethnicity 4.3.3.5 Nine-digit ZIP code 4.3.3.6 Method of payment 4.4 Eligibility Verification Patients must meet all of the eligibility requirements listed in Section 3.0. An eligibility checklist has been appended to the protocol. A confirmation of registration will be forwarded by the ECOG Coordinating Center. 4.5 Stratification Factors 4.5.1 AJCC Stage 4.5.1.1 Unresectable 4.5.1.2 M1a/1b 4.5.1.3 M1c 4.5.2 Prior Therapy 4.5.2.1 None 4.5.2.2 IFN Rev. 4/11 4.5.2.3 One investigational therapy or one systemic therapeutic regimen (See Section 3.2) 4.6 Additional Requirements 4.6.1 Patients must provide a signed and dated written informed consent form. Rev. 4/12 4.6.2 Diagnostic pathology materials must be submitted as indicated in Section 10 for central review. Rev. 4/12 4.6.3 Blood samples and post therapy pathology samples are to be submitted for banking per patient consent as indicated in Sections 10 and 11. NOTE: ECOG requires that biological samples submitted from patients participating in E1608 be entered and tracked via the online ECOG Sample Tracking System (STS). Any case reimbursements associated with sample submissions may not be captured if samples are not logged into STS. See Section 11.5.
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Rev. 4/11 4.6.4 Additional Registration Training Requirement Mandatory Investigator Training Course ECOG has developed a training course to provide additional information to enrolling investigators on the toxicity profile of ipilimumab. Each investigator is required to review the slide deck titled: E1608 Ipilimumab Immune Related Adverse Events: Summary and Recommended Management, prior to their first patient enrollment by accessing the following URL: http://coccg.mindflash.com/PublicCoursePage.aspx?CourseId=16548895 Rev. 4/12 Patient enrollments will be blocked via the OPEN system if the enrolling investigator has not completed the required training. If your site has a patient waiting and the enrolling INV completed the training after the hours of 9AM-5:30PM ET Monday – Friday, please email the ECOG Ipi Education Team at [email protected] for after hours assistance. 4.7 Instructions for Patients who Do Not Start Assigned Protocol Treatment If a patient does not receive any assigned protocol treatment, baseline and follow-up data will still be collected and must be submitted according to the instructions in the E1608 Forms Packet. Document the reason for not starting protocol treatment on the off treatment form. Also report the date and type of the first non-protocol treatment that the patient receives.
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4.8 Investigator’s Drug Brochure and Safety Alerts GM-CSF is an INVESTIGATIONAL AGENT. A copy of the Investigator’s Brochure (IB) is available for download from the ECOG webpage. The IB provides relevant and current scientific information about the investigational product. The IB should be submitted to your IRB/EC according to GCP regulations. The IDB and any correspondence to the Institutional Review Board (IRB)/Ethics Committee (EC) should be kept in the E1608 regulatory files. Ipilimumab is an INVESTIGATIONAL AGENT (IND# 10200). A copy of the Investigator's Brochure (IB) can be obtained by calling the Pharmaceutical Management Branch at the NCI (301/496-5725) or via email request to [email protected]. NOTE: Please have your investigator’s NCI # handy. The IB provides relevant and current scientific information about the investigational product. Please submit the IB to your IRB/EC according to GCP regulations. The IB and any correspondence to the IRB should be kept in the study files of E1608. Should any SAE report on this study qualify as a safety alert report requiring expedited reporting, the SAE report will be sent by the sponsors to regulatory authorities globally (including the FDA) and ECOG. If applicable, ECOG will disseminate these safety alert reports to all ECOG investigators in the bimonthly group mailings. These reports should be forwarded to your IRB/EC within 90 days of receipt for review. Reporting instructions are provided with each safety alert. These safety alerts and any correspondence to your IRB/EC should be maintained in your E1608 study files.
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5. Treatment Plan
5.1 Administration Schedule Patients will be randomized to one of the following arms: 5.1.1 Arm A 1 cycle= 21 days. 5.1.1.1 Induction Therapy - Cycles 1-4 *GM-CSF 250 mcg subcutaneous Q Day, Days 1-14 of each cycle plus
Rev. 4/12 Ipilimumab 10 mg/kg IV, Day 1 of cycles 1-4 5.1.1.2 Maintenance Therapy - Cycles 5 and Higher *GM-CSF 250 mcg subcutaneous Q Day, Days 1-14 of each cycle plus Rev. 4/12 Ipilimumab 10 mg/kg IV, Day 1 every 4th cycle (12 weeks) starting with cycle 8 *NOTE: Patients will self-administer doses of GM-CSF. Patients will be taught how to self-inject subcutaneously and be advised to record their daily doses in their “patient diary.” 5.1.2 Arm B 1 cycle= 21 days. 5.1.2.1 Induction Therapy - Cycles 1-4 Rev. 4/12 Ipilimumab 10 mg/kg IV, Day 1 of cycles 1-4 5.1.2.2 Maintenance Therapy - Cycles 5 and Higher Rev. 4/12 Ipilimumab 10 mg/kg IV, Day 1 every 4th cycle (12 weeks) starting with cycle 8 NOTE: For preparation and administration guidelines for ipilimumab, see Section 8.1.8. NOTE: Ipilumumab infusions should be given over 90 minutes (not bolus or IV push) 5.2 Dose Calculations for Ipilimumab Calculate Total Dose as follows: Patient actual body weight in kg x [10 mg study dose] = total dose in mg Calculate Total Infusion Volume as follows: Total dose in mg ÷ 5 mg/mL = infusion volume in mL Calculate Rate of Infusion as follows: Infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. For example, a patient weighing 114 kg (250 lb) would be administered 1140 mg of ipilimumab (114 kg x 10 mg/kg = 1140 mg) with an infusion volume of 228 mL (1140 mg ÷ 5 mg/mL = 228 mL) at a rate of approximately 2.5 mL/min (228 mL ÷ 90 minutes) in 90 minutes.
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5.3 Adverse Event Reporting Requirements 5.3.1 Purpose Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial (please refer to the E1608 Forms Packet for the list of forms with directions for routine adverse event reporting). Additionally, certain adverse events must be reported in an expedited manner for more timely monitoring of patient safety and care. The following sections provide information about expedited reporting. Rev. 4/12 5.3.2 Determination of Reporting Requirements Reporting requirements may include the following considerations: 1) whether the patient has received an investigational or commercial agent; 2) the characteristics of the adverse event including the grade (severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of the adverse event; 3) the phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated with the event. An investigational agent is a protocol drug administered under an Investigational New Drug Application (IND). In some instances, the investigational agent may be available commercially, but is actually being tested for indications not included in the approved package label. Steps to determine if an adverse event is to be reported in an expedited manner: Step 1: Identify the type of event: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). Step 2: Grade the event using the NCI CTCAE v. 4.0. Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite.
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Step 4: Determine the prior experience of the adverse event. Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either the type of event or the severity of the event is NOT listed in:
Rev. 10/11 • Arm A and B – the current NCI Specific Protocol Exceptions to Expedited Reporting (SPEER) for the CTEP investigational agent (Ipilimumab).
Rev. 10/11 NOTE: The NCI Specific Protocol Exceptions to Expedited Reporting (SPEER) is included in section 5.4 of the protocol. The SPEER is presented in the last column of the CAEPR and identified with bold and italicized text. The SPEER is a list of events that are exceptions to expedited reporting via AdEERS. Events listed in the SPEER column should ONLY be reported via AdEERS if they exceed the grade noted in parentheses next to the AE in the SPEER. NOTE: For general questions regarding expedited reporting requirements, please contact the NCI AdEERS Help Desk: 301-897-7497. Rev. 4/12 5.3.3 Reporting Procedure This study requires that expedited adverse event reporting use the NCI’s Adverse Event Expedited Reporting System (AdEERS). The NCI’s guidelines for AdEERS can be found at http://ctep.cancer.gov. An AdEERS report must be submitted electronically to ECOG and the appropriate regulatory agencies via the AdEERS Web-based application located at http://ctep.cancer.gov. In the rare event when Internet connectivity is disrupted a 24-hour notification is to be made by telephone to • the AE Team at ECOG (617-632-3610) and • the NCI (301-897-7497) An electronic report MUST be submitted immediately upon re-establishment of internet connection. Supporting and follow up data: Any supporting or follow up documentation must be faxed to ECOG (617-632-2990), Attention: AE within 48-72 hours. In addition, supporting or follow up documentation must be faxed to the NCI (301-230-0159).) in the same timeframe. NCI Technical Help Desk: For any technical questions or system problems regarding the use of the AdEERS application, please contact the NCI Technical Help Desk at [email protected] or by phone at 1-888-283-7457 or 301-840- 8202 5.3.4 When to report an event in an expedited manner Some adverse events require 24-hour notification (refer to Section 5.3.6). Please complete a 24-Hour Notification Report via the NCl AdEERS website (http://ctep.cancer.gov/reporting/adeers.html) within 24 hours of learning of the event. The full AdEERS report must be completed and submitted via AdEERS within 5 calendar days.
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If the AdEERS system is down, a 24-hour notification call must be made to ECOG (617-632-3610) and to NCI (301-897-7497). Once the system is restored, a 24-hour Notification Report must be entered into the AdEERS system by the original submitter of the report at the site. When an adverse event requires expedited reporting, submit a full AdEERS report within the timeframes outlined in Section 5.3.6. NOTE: Adverse events that meet the reporting requirements in Section 5.3.6 and occur within 30 days of the last dose of protocol treatment must be reported on an expedited adverse event report form (using AdEERS). For any adverse events that occur more than 30 days after the last dose of treatment, only those that have an attribution of possibly, probably, or definitely AND meet the reporting requirements in Section 5.3.6 must be reported on an expedited adverse event report form (using AdEERS). 5.3.5 Other recipients of adverse event reports DCTD/NCI will notify ECOG/pharmaceutical collaborator(s) of all AEs reported to FDA. Any additional written AE information requested by ECOG MUST be submitted to BOTH the NCI and ECOG. Adverse events determined to be reportable must also be reported by the institution, according to the local policy and procedures, to the Institutional Review Board responsible for oversight of the patient. 5.3.6 Expedited reporting for investigational agents Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND: AdEERS Expedited Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of Investigational Agent (Ipilimumab) in this Study (Arm A and B) OR Within 30 Days of the Last Dose of Any Protocol Treatment.
Grades Grades Grade 1 Grade 2 Grade 2 Grade 3 Grade 3 4 & 52 4 & 52 Unexpected Expected Unexpected
Attribution and with without with without Unexpected Expected Unexpected Expected Expected Hospitali- Hospitali- Hospitali- Hospitali- zation zation zation zation 10 10 Unrelated Not Not Not Not Not 10 Calendar 10 Calendar Calendar Calendar Unlikely Required Required Required Required Required Days Days Days Days Possible 10 10 10 24-Hour; Not 10 Calendar Not Not 10 Calendar Probable Calendar Calendar Calendar 5 Calendar Required Days Required Required Days Definite Days Days Days Days 1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment with an agent under a CTEP IND require reporting as follows: AdEERS 24-hour notification followed by complete report within 5 calendar days for: • Grade 4 and Grade 5 unexpected events AdEERS 10 calendar day report: • Grade 3 unexpected events with hospitalization or prolongation of hospitalization • Grade 5 expected events 2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table.
Please see additional information below under section entitled “Additional instructions, requirements, and exceptions for protocol E1608.” March 2005
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NOTE: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause should be provided. • Expedited AE reporting timelines: ¾ 24 Hours; 5 calendar days – The investigator must initially report the AE via AdEERS within 24 hours of learning of the event followed by a complete AdEERS report within 5 calendar days of the initial 24-hour report. ¾ 10 calendar days – A complete AdEERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event. • Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization* (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions. • Any event that results in persistent or significant disability/incapacity, congenital anomaly, or birth defect must be reported via AdEERS if the event occurs following treatment with an agent under a CTEP IND. • Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports. * Hospitalizations are defined as lasting 24 hours or longer and these events must be reported via AdEERS.
Rev. 4/12 Additional instructions, requirements and exceptions for protocol E1608 1. Additional Instructions: ¾ With respect to determining the specific day by which the event must be reported, the day the reporter learns of the adverse event constitutes “Day 0.” ¾ For instructions on how to specifically report events that result in persistent or significant disability/incapacity, congenital anomaly, or birth defect events via AdEERS, please contact the NCI AdEERS Help Desk at 301-897-7497 or [email protected]. 2. ECOG and Protocol Specific expedited reporting requirements: The adverse events listed below also require expedited reporting for this trial: ECOG specific expedited reporting requirements: ¾ Hospitalizations: Any grade 1 or 2 adverse event with precipitates a hospitalization lasting > 24 hours (or prolongs hospitalization) must be reported via AdEERS within 10 calendar days of learning of the event regardless of the attribution and designation as expected or unexpected. Protocol specific expedited reporting requirements: ¾ Bowel Perforation: Any grade 3 or higher bowel perforation must be reported via AdEERS within 10 calendar days of learning of the event regardless of the attribution and designation as expected or unexpected.
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¾ Immune Related Adverse Events: Any grade 3 or higher immune related adverse event (see section 5.5.3 for definition) must be reported via AdEERS within 10 calendar days of learning of the event regardless of the attribution and designation as expected or unexpected. ¾ Pregnancies: All confirmed pregnancies occurring while on protocol treatment must be reported via AdEERS. Please report the pregnancy as a grade 4 event, using the category “Reproductive System – other”. The initial AdEERS report is required to be sent as a 24-hour notification followed by a complete report within 5 calendar days.
5.3.7 Reporting Secondary Primary Cancers
Rev. 4/12 All cases of second primary cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), that occur following treatment on NCI-sponsored trials must be reported to ECOG. Rev. 4/12 • A second malignancy is a cancer that is UNRELATED to any prior anti- cancer treatment (including the treatment on this protocol). Second malignancies require ONLY routine reporting as follows: 1. Submit a completed ECOG Second Primary Form within 30 days to ECOG at ECOG Coordinating Center FSTRF 900 Commonwealth Avenue Boston, MA 02215 2. Submit a copy of the pathology report to ECOG confirming the diagnosis. 3. If the patient has been diagnosed with AML/MDS, submit a copy of the cytogenetics report (if available) to ECOG Rev. 4/12 • A secondary malignancy is a cancer CAUSED BY any prior anti-cancer treatment (including the treatment on this protocol). Secondary malignancies require both routine and expedited reporting as follows: 1. Submit a completed ECOG Second Primary Form within 30 days to ECOG at ECOG Coordinating Center FSTRF 900 Commonwealth Avenue Boston, MA 02215 2. Report the diagnosis via AdEERS at http://ctep.cancer.gov Report under a.) leukemia secondary to oncology chemotherapy, b.) myelodysplastic syndrome, or c.) treatment related secondary malignancy 3. Submit a copy of the pathology report to ECOG and NCI/CTEP confirming the diagnosis. 4. If the patient has been diagnosed with AML/MDS, submit a copy of the cytogenetics report (if available) to ECOG and NCI/CTEP.
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NOTE: The ECOG Second Primary Form and the AdEERS report should not be used to report recurrence or development of metastatic disease. NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the ECOG Second Primary Form must be submitted for the most recent trial. ECOG must be provided with a copy of the form and the associated pathology report and cytogenetics report (if available) even if ECOG was not the patient's most recent trial. NOTE: Once data regarding survival and remission status are no longer required by the protocol, no follow-up data should be submitted via AdEERS or by the ECOG Second Primary Form.
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Rev. 10/11 5.4 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Ipilimumab (MDX-010, NSC 732442) The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via AdEERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ae guidelines.pdf for further clarification. Frequency is provided based on 2678 patients. Below is the CAEPR for ipilimumab (MDX-010). Rev. 4/12 NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER. Version 2.4, August 24, 20111
Adverse Events with Possible Specific Protocol Relationship to Ipilimumab (MDX-010) Exceptions to Expedited (CTCAE 4.0 Term) Reporting (SPEER) [n= 2678] (formerly known as ASAEL) Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%) BLOOD AND LYMPHATIC SYSTEM DISORDERS Blood and lymphatic system disorders - Other (acquired hemophilia) CARDIAC DISORDERS Atrial fibrillation Myocarditis2 ENDOCRINE DISORDERS Adrenal insufficiency2 Endocrine disorders - Other (hypopituitarism/hypophysitis)2 Endocrine disorders - Other (testosterone deficiency)2 Hyperthyroidism2 Hypothyroidism2 EYE DISORDERS Eye disorders - Other (episcleritis) Uveitis GASTROINTESTINAL DISORDERS Abdominal pain Colitis2 Colitis (Gr. 1) Colonic perforation3 Constipation Diarrhea Diarrhea (Gr. 2) Enterocolitis Esophagitis Ileus
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Nausea Nausea (Gr. 3) Pancreatitis2 Vomiting GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Fatigue Fatigue (Gr. 3) Fever Fever (Gr. 3) Infusion related reaction Multi-organ failure HEPATOBILIARY DISORDERS Hepatobiliary disorders – Other (hepatitis)2 IMMUNE SYSTEM DISORDERS Autoimmune disorder2 INFECTIONS AND INFESTATIONS Infections and infestations - Other (aseptic meningitis)2 INVESTIGATIONS Alanine aminotransferase increased Aspartate aminotransferase increased Neutrophil count decreased METABOLISM AND NUTRITION DISORDERS Anorexia Dehydration MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Arthritis Musculoskeletal and connective tissue disorder - Other (polymyositis)2 NERVOUS SYSTEM DISORDERS Facial nerve disorder Headache Nervous system disorders - Other (Guillain-Barre syndrome)2 Nervous system disorders - Other (myasthenia gravis)2 RENAL AND URINARY DISORDERS Acute kidney injury Renal and urinary disorders - Other (granulomatous tubulointerstitial nephritis) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Pneumonitis SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema multiforme Pruritus Pruritus (Gr. 3) Rash maculo-papular Rash maculo-papular (Gr. 2) Stevens-Johnson syndrome Urticaria VASCULAR DISORDERS Hypotension
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1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting [email protected]. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell activation and proliferation. These can include (but are not limited to) autoimmune hemolytic anemia, acquired anti- factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome. The majority of these reactions manifested early during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of additional treatments. 3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with subsequent IL-2 therapy. 4In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 5Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 6Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. Also reported on ipilimumab (MDX-010) trials but with the relationship to ipilimumab (MDX-010) still undetermined: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - Other (pure red cell aplasia)2; Febrile neutropenia CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy EYE DISORDERS - Extraocular muscle paresis4; Eye disorders - Other (retinal pigment changes) GASTROINTESTINAL DISORDERS - Dyspepsia; Dysphagia; Gastrointestinal hemorrhage5 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac chest pain HEPATOBILIARY DISORDERS - Hepatic failure2 IMMUNE SYSTEM DISORDERS - Allergic reaction INFECTIONS AND INFESTATIONS - Infection6 INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; Platelet count decreased; Serum amylase increased; Weight loss; White blood cell decreased METABOLISM AND NUTRITION DISORDERS - Metabolism and nutrition disorders - Other (exacerbation of pre-existing diabetes mellitus) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion decreased; Myalgia; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Peripheral sensory neuropathy; Seizure PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia RENAL AND URINARY DISORDERS - Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; Laryngospasm SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Skin hypopigmentation VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis) Note: Ipilimumab (MDX-010) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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5.5 Dose Modifications
All toxicity grades below are described using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov ). NOTE: There will be no dose changes for ipilimumab, but the timing of the dose can be modified as described below.
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Patients may develop study drug-related toxicities that may require skipping doses or dose discontinuation. Some of these adverse events may be consistent with potentially drug- related immune-mediated phenomena; termed IRAEs (See Appendix IV). Details of how to dose study medication in the present of adverse drug reactions that may or may not be IRAEs are addressed below. Treatment modifications will be made based on specified safety criteria. Patients will delay or discontinue treatment with ipilimumab if they experience at least one adverse event, specified below, considered by the investigator to be definitely, probably, or possibly related to ipilimumab treatment. The following criteria will be used to determine dosing delay, restarting doses, or discontinuing ipilimumab. Delay ipilimumab dosing for the following related adverse events: • Any > Grade 2 non-skin related adverse event (including IRAEs), except for laboratory abnormalities. • Any > Grade 3 skin related adverse events regardless of causality (including IRAEs). Resolution to grade 1 or better required before continuing treatment. • Further with regards to skin rashes, all study drugs should be held as well as any Rev. 4/11 other agents possibly associated with toxic epidermal necrolysis (TEN) or Stevens- Johnson Syndrome (SJS) until an evaluation has been done. This would include any patient with possible erythema multiforme (EM) or SJS and for any grade 2 purpuric or bullous rash. • Any > Grade 3 laboratory abnormality believed to be related to study treatment.
Rev. 4/11 • All study drugs should be held for suspected colitis until an appropriate evaluation has been completed. Please refer to Appendix V for Diarrhea Management Algorithm. • Patients who develop hypophysitis may continue treatment once they are on a stable replacement regimen. Please refer to Appendix VII Endocrinopathies Management Algorithm. • Patients with hepatitis may continue once their liver function tests resolve to pretreatment grade. Please refer to Appendix VI Hepatotoxicity Management Algorithm for management recommendations. Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to ≤ Grade 1 severity or returns to baseline within 2 weeks of initial dose administration: • If the adverse event has resolved, restart ipilimumab dosing at the next scheduled time point per protocol. • If the adverse event has not resolved in the protocol-specified dosing window (3 weeks [+/- 3 days]), the next scheduled dose will be omitted. • If > 1 dose is expected to be skipped, the dosing schedule modifications must be discussed with the primary investigator (or co-primary investigator, if the PI is not available) prior to implementation. • Drug may be restarted following any grade 2 or greater autoimmune event after complete resolution of symptoms and underlying pathology.
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5.5.1 Permanent Discontinuation of Ipilimumab 5.5.1.1 Permanent Discontinuation for Related Adverse Events • Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to topical therapy and does not improve to ≤ Grade 1 severity within 2 weeks of starting therapy, OR, requires systemic treatment. • Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction. • Any other ≥ Grade 3 non-skin related adverse event with the exception of events listed in section 5.5.1.2. • Any adverse event, laboratory abnormality or intercurrent illness which, in the judgment of the investigator, presents a substantial clinical risk to the patient with continued dosing. • Grade 3 uveitis • All grade 3 or greater autoimmune events should be taken off treatment with the exception listed in Section 5.5.1.2. 5.5.1.2 Exceptions to Permanent Discontinuation • Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor reaction and a potential therapeutic response. This includes inflammatory reactions at sites of tumor resections or in draining lymph nodes, or at sites suspicious for, but not diagnostic of metastasis. • Hospitalization for ≤ Grade 2 adverse events where the primary reason for hospitalization is to expedite the clinical work-up. • Patients with the following conditions where in the investigator’s opinion continuing study drug administration is justified: − Ocular toxicity that has responded to topical therapy. − Endocrinopathies where clinical symptoms are controlled with appropriate hormone replacement therapy. Note: Ipilimumab may not be restarted while the patient is being treated with systemic corticosteroids except for patients on stable doses of hormone replacement therapy such as hydrocortisone. 5.5.2 GM-CSF Dose Modifications 5.5.2.1 Patients with documented WBC > 60,000/mm3 will have subsequent GM- CSF doses reduced by 50% of the current dose at the start of the next cycle. This is a permanent dose reduction. 5.5.2.2 Any grade 3 toxicity believed to be secondary to GM-CSF requires a 50% dose reduction of the current dose at the start of the next cycle. These are permanent dose reductions. If toxicity of this severity occurs after dose reduction, the GM-CSF is discontinued permanently. 5.5.2.3 GM-CSF is to be discontinued permanently for any major organ toxicity believed to be due to GM-CSF. Any reaction judged by the investigator to be an acute allergic reaction to GM-CSF (i.e., severe enough to require intervention) requires that GM-CSF be discontinued permanently. Ipilimumab may be continued if there is resolution of adverse events within the guidelines to continue ipilimumab therapy and if patients can receive benefit from continued treatment.
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Acetominophen prior to GM-CSF injection is permitted for patients who experience mild symptoms such as puritis or headache. 5.5.3 Immune-Related Adverse Events (IRAEs): Definition, Monitoring, and Treatment Blocking CTLA-4 function may permit the emergence of auto-reactive T cells and resultant clinical autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, and hypopituitarism were drug-related, presumptive autoimmune events, now termed IRAEs, noted in previous ipilimumab studies. For the purposes of this study, an IRAE is defined as an AE of unknown etiology associated with drug exposure and consistent with an immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an AE an IRAE. Serological, immunological, and histological (biopsy) data should be used to support the diagnosis of an immune-mediated toxicity. Suspected IRAEs must be documented on an AE or SAE form. Patients should be informed of and carefully monitored for evidence of clinically significant systemic IRAE (e.g., systemic lupus erythematosus-like diseases) or organ-specific IRAE (e.g., rash, colitis, uveitis, hepatitis or thyroid disease). If an IRAE is noted, appropriate work-up (including biopsy if possible) should be performed, and steroid therapy may be considered if clinically necessary. See Appendix IV for suggested work-up and treatment of IRAEs. It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab activity. However, clinical anti-tumor responses have been maintained in patients treated with corticosteroids and discontinued from ipilimumab. If utilized, corticosteroid therapy should be individualized for each patient. Prior experience suggests that colitis manifested as ≥ Grade 3 diarrhea requires corticosteroid treatment. See Appendix V for additional details. 5.5.4 Other Guidance 5.5.4.1 Treatment of Infusion Reactions Associated with Ipilimumab Since ipilimumab contains only human protein sequences, it is less likely that any allergic reaction will be seen in patients. However, it is possible that infusion of ipilimumab will induce a cytokine release syndrome that could be evidenced by fever, chills, rigors, rash, pruritis, hypotension, hypertension, bronchospasm, or other symptoms. No prophylactic pre-medication will be given unless indicated by previous experience in an individual patient. Reactions should be treated based upon the following recommendations. • For mild symptoms (e.g., localized cutaneous reactions such as mild pruritis, flushing, rash): − Decrease the rate of infusion until recovery from symptoms, remain at bedside and monitor patient. − Complete the ipilimumab infusion at the initial planned rate. − Diphenhydramine 50 mg IV may be administered at the discretion of the treating physician and patients may receive additional doses with close monitoring. − Premedication with diphenhydramine may be given at the discretion of the investigator for subsequent doses of ipilimumab.
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• For moderate symptoms (any symptom not listed above [mild symptoms] or below [severe symptoms] such as generalized pruritis, flushing, rash, dyspnea, hypotension with systolic BP >80 mmHg): − Interrupt ipilimumab. − Administer diphenhydramine 50 mg IV. − Monitor patient closely until resolution of symptoms. − Corticosteroids may abrogate any beneficial immunologic effect, but may be administered at the discretion of the treating physician. − Resume ipilimumab infusion after recovery of symptoms. − At the discretion of the treating physician, ipilimumab infusion may be resumed at one half the initial infusion rate, then increased incrementally to the initial infusion rate. − If symptoms develop after resumption of the infusion, the infusion should be discontinued and no additional ipilimumab should be administered that day. − The next dose of ipilimumab will be administered at its next scheduled time and may be given with pre-medication (diphenhydramine and acetaminophen) and careful monitoring, following the same treatment guidelines outlined above. − At the discretion of the treating physician additional oral or IV antihistamine may be administered prior to dosing with ipilimumab. • For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, systolic blood pressure <80 mm Hg, or angioedema): − Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from the subject. − Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. − Patients should be monitored until the investigator is comfortable that the symptoms will not recur. − No further ipilimumab will be administered. • In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week after treatment of a localized or generalized pruritis), symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids). 5.5.4.2 Treatment of Ipilimumab-Related Isolated Drug Fever In the event of isolated drug fever, the investigator must use clinical judgment to determine if the fever is related to the ipilimumab or to an infectious etiology. If a patient experiences isolated drug fever, for the next dose, pre-treatment with acetaminophen or non-steroidal anti-inflammatory agent (investigator discretion) should be instituted and a repeated antipyretic dose at 6 and 12 hours after ipilimumab infusion, should be administered. The infusion rate will remain unchanged for future doses. If a patient experiences recurrent isolated drug fever following premedication and post dosing with an appropriate antipyretic, the infusion rate for
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subsequent dosing should be decreased to 50% of the previous rate. If fever recurs following infusion rate change, the investigator should assess the patient’s level of discomfort with the event and use clinical judgment to determine if the patient should receive further ipilimumab. 5.6 Prohibited and Restricted Therapies During the Study 5.6.1 Prohibited Therapies Patients in this study may not use vaccines for the treatment of cancer or prevention of disease unless indicated as a component of the protocol regimen (including those for common medical conditions) for up to one month pre and post dosing with ipilimumab. Concomitant systemic or local anti-cancer medications or treatments are prohibited in this study while receiving ipilimumab treatments. Patients may not use any of the following therapies during the study: • Any non-study anti-cancer agent (investigational or non-investigational) • Any other investigational agents • Any other (non-CA184024 related) CTLA-4 inhibitors or agonists • CD137 agonists • Immunosuppressive agents • Chronic systemic corticosteroids • Physiologic replacement doses of corticosteroids are permitted if required • Any non-oncology vaccine therapies used for the prevention of infectious diseases (for up to 30 days prior to or after any dose of study drug) 5.6.2 Precautions Caution is advised when considering treatment with high-dose IL-2 in patients who have previously been administered ipilimumab, particularly in patients who experienced ipilimumab-related diarrhea/colitis. Colonoscopy or sigmoidoscopy with biopsy may be advisable prior to IL-2 administration once the patient is no longer receiving ipilimumab. 5.7 Supportive Care 5.7.1 All supportive measures consistent with optimal patient care will be given throughout the study. 5.7.2 Please refer to Appendices V-VII for algorithms pertaining to immune related adverse events. 5.8 Duration of Therapy Patients will receive protocol therapy unless: 5.8.1 Extraordinary Medical Circumstances If at any time the constraints of this protocol are detrimental to the patient's health, protocol treatment should be discontinued. This includes any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of the investigator, indicates that continued treatment with study therapy is not in the best interest of the subject. In this event submit forms according to the instructions in the E1608 Forms Packet. 5.8.2 Patient withdraws consent
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5.8.3 Pregnancy All WOCBP should be instructed to contact the investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study participation. Pregnancy tests should be conducted per Section 7.1 of the protocol or as clinically indicated. All confirmed pregnancies must be reported according to the instructions in Section 5.3. 5.8.4 Progression of disease after 12 weeks of treatment See Section 6.2.5. NOTE: Patients who progress clinically at or before the 12th week of treatment will discontinue protocol therapy if other therapy (surgery, radiation, chemotherapy) is needed urgently. However, patients who experience progression of disease that does not require urgent change in therapy are eligible to receive 24 weeks of treatment. 5.9 Duration of Follow-up For this protocol, all patients, including those who discontinue protocol therapy early, will be followed for response until progression, and for survival for 5 years from the date of registration. All patients must also be followed through completion of all protocol therapy.
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6. Measurement of Effect
6.1 Antitumor Effect – Solid Tumors For the purposes of this study, patients should be re-evaluated for response every 12 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in RECIST. The following general principles must be followed: 1. To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than four weeks before registration. 2. Measurable disease is defined by the presence of at least one measurable lesion. 3. All measurements should be recorded in metric notation by use of a ruler or calipers. 4. The same method of assessment and the same technique must be used to characterize each identified lesion at baseline and during follow-up. 6.1.1 Definitions Evaluable for Objective Response Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target lesion assessment. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 6.1.2 Disease Parameters Measurable Disease Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters. NOTE: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable.
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Malignant Lymph Nodes To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable Disease All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with > 10 to < 15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Non-measurable also includes lesions that are < 20 mm by chest x-ray. NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non- measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target Lesions All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum of the diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target Lesions All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of unequivocal progression of each should be noted throughout follow-up.
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6.1.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before registration. The same method of assessment and the same technique must be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical Lesions Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest X-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is not an acceptable method of evaluation in RECIST studies. PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint.
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Tumor Markers Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. Cytology, Histology These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. 6.1.4 Response Criteria 6.1.4.1 Evaluation of Target Lesions Complete Response (CR) Rev. 4/12 Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. To be assigned a status of complete response, changes in tumor measurements must be confirmed by a repeat assessment performed no less than four weeks after the criteria for response is met. Partial Response (PR) Rev. 4/12 At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. To be assigned a status of partial response, changes in tumor measurements must be confirmed by a repeat assessment performed no less than four weeks after the criteria for response is met. Progressive Disease (PD) At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression, See Section 6.1.4.3). Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. (Note: a change of 20% or less that does not increase the sum of the diameters by 5 mm or more is coded as stable disease) To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 12 weeks.
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6.1.4.2 Evaluation of Non-Target Lesions Complete Response (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) NOTE: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions (see Section 6.1.4.3). Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. When the patient also has measurable disease, there must be an overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size of one or more on-target lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare. When the patient only has non-measurable disease, the increase in overall disease burden should be comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e., an increase in tumor burden from “trace” to “large”, an increase in nodal disease from “localized” to “widespread”, or an increase sufficient to require a change in therapy. Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 6.1.4.3 Evaluation of New Lesions The appearance of new lesions constitutes Progressive Disease (PD).
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6.1.4.4 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence or non-protocol therapy (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. For Patients with Measurable Disease (i.e., Target Disease)
Best Target Non-Target New Overall Remarks Lesions Lesions Lesions* Response CR CR No CR CR Non-CR/Non-PD No PR CR Not evaluated No PR
Non-PD/not PR No PR evaluated Documented at least Non-PD/not SD No SD once > 12 wks. from evaluated study entry PD Any Yes or No PD Any PD** Yes or No PD No prior SD, PR or CR Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document the objective progression even after discontinuation of treatment.
Duration of Response Duration of Overall Response The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.
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Duration of Stable Disease Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 12 weeks. 6.2 Evaluation of Patient's Best Overall Response The best overall response is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The table below provides overall responses for all possible combinations of tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Rev. 4/12 To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of at least 12 weeks. Overall Response for all Possible Combinations of Tumor Response Target Lesions Nontarget Lesions New Lesions Overall Response CR CR No CR CR Incomplete response/SD No PR PR Non-PD No PR SD Non-PD No SD PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 6.2.1 First Documentation of Response The time between initiation of therapy and first documentation of PR or CR. 6.2.2 Confirmation of Response To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. 6.2.3 Duration of Response Duration of overall response – the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, taking as reference the smallest measurements recorded since treatment started. 6.2.3.1 Duration of Overall Complete Response The period measured from the time measurement criteria are met for complete response until the first date that recurrent disease is objectively documented.
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Rev. 4/12 6.2.3.2 Duration of Stable Disease A measurement from registration until the actual date the criteria for disease progression is met, taking as reference the smallest measurements recorded since registration. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval, not less than 12 weeks. 6.2.4 Definition of Tumor Response Using irRC NOTE: This section is for secondary endpoint assessment. The sum of the products of the two largest diameters of lesions (SPD) at tumor assessment using the immune-related response criteria (irRC) for progressive disease incorporates the contribution of new measurable lesions. Each net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the size and growth kinetics of both old and new lesions as they appear. 6.2.4.1 Definition of Target Lesions Response Using irRC • irComplete Response (irCR): Complete disappearance of all target lesions. This category encompasses exactly the same subjects as “CR” by the mWHO criteria. • irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all target and all new measurable lesions (i.e., Percentage Change in Tumor Burden). Note: the appearance of new measurable lesions is factored into the overall tumor burden, but does not automatically qualify as progressive disease until the SPD increases by > 25% when compared to SPD at nadir. • irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease. • irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e., taking SPD of all target lesions and any new lesions) when compared to SPD at nadir. 6.2.4.2 Definition of Non-Target Lesions Response Using irRC • irComplete Response (irCR): Complete disappearance of all non- target lesions. This category encompasses exactly the same subjects as “CR” by the mWHO criteria. • irPartial Response (irPR): Non-target lesion(s) are not considered in Rev. 4/11 the definition of PR; this term does not apply. Rev. 4/11 • irStable Disease (irSD): Does not meet the criteria for irCR or irPD. • irProgressive Disease (irPD): Increases in number or size of non- target lesion(s) does not constitute progressive disease unless/until the Percentage Change in Tumor Burden increases by 25% (i.e., the SPD at nadir of the target lesions increases by the required amount). 6.2.4.3 Impact of New Lesions on irRC New lesions in and by themselves do not qualify as progressive disease. However their contribution to total tumor burden is included in the SPD which in turn feeds into the irRC criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any subject from the study.
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6.2.4.4 Definition of Overall Response Using irRC Overall response using irRC will be based on these criteria: • Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions (target and non-target together with no new measurable/unmeasurable lesions) for at least 4 weeks from the date of documentation of complete response. • Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all target lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is considered an immune Partial Response (irPR). • Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for immune complete response or immune partial response, in the absence of progressive disease. • Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to confirm PD by serial imaging. Any of the following will constitute progressive disease: − At least 25% increase in the SPD of all target lesions over nadir SPD calculated for the target lesions. − At least a 25% increase in the SPD of all target lesions and new measurable lesions (irSPD) over the nadir SPD calculated for the target lesions. Table 3: Immune-Related Response Criteria Definitions
Percent change in Target Non-Target New New Overall tumor burden (including Lesion Lesion Measurable Unmeasurable measurable new lesions irRC Definition Definition Lesions Lesions when present) Response Complete Complete No No –100% irCR Response Response Partial Any Any Any > –50% irPR Response <–50% to <+25% irSD >+25% irPD Stable Any Any Any <–50% to <+25% irSD Disease >+25% irPD Progressive Any Any Any >+25% irPD Disease
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6.2.4.5 Immune-Related Best Overall Response Using irRC (irBOR) irBOR is the best confirmed irRC overall response over the study as a whole, recorded between the date of first dose until the last tumor assessment before subsequent therapy (except for local palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the assessment of irBOR, all available assessments per subject are considered. irCR or irPR determinations included in the irBOR assessment must be confirmed by a second (confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks after the criteria for response are first met. 6.2.5 Response Endpoints Ipilimumab is expected to trigger immune-mediated responses, which require activation of the immune system prior to the observation of clinical responses. Such immune activation may take weeks to months to be evident. Some patients may have objective volume increase of tumor lesions or other disease parameters (based on study indication, ie, hematologic malignancies) within 12 weeks following start of ipilimumab dosing. Such patients may not have had sufficient time to develop the required immune activation or, in some patients, tumor volume or other disease parameter increases may represent infiltration of lymphocytes into the original tumor or blood. In conventional studies, such tumor volume or relevant laboratory parameter increases during the first 12 weeks of the study would constitute PD and lead to discontinuation of imaging to detect response, thus disregarding the potential for subsequent immune-mediated clinical response. Therefore, patients with tumor volume increase detected or lack of laboratory parameter response documentation prior to week 12 but without rapid clinical deterioration should continue to be treated with ipilimumab and clinically observed with a stringent imaging schedule to allow detection of a subsequent tumor response. Patients may continue treatment with disease progression by RECIST at the discretion of the treating physician and in the absence of a declining performance status as long as there is less than 100% increase in tumor burden from beginning of treatment and less than 25% increase in tumor burden during maintenance ipilimumab from staging following induction ipilimumab inclusive of potentially new lesions. Patients may continue to be treated in this scenario in the absence for the need for additional treatment, including any new CNS lesions that require immediate treatment. This will improve the overall assessment of the clinical activity or ipilimumab and more likely capture its true potential to induce clinical responses. Tumor assessments will be made using RECIST criteria. 6.2.6 Survival Survival will be measured from the date of entry on study. 6.2.7 Time to Progression This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression.
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6.2.8 Methods of Measurement Imaging based evaluation is preferred to evaluation by clinical examination. The same imaging modality must be used throughout the study to measure disease. 6.2.8.1 CT and MRI CT and magnetic resonance imaging (MRI) are the best currently available and most reproducible methods for measuring target lesions. Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT should be performed by use of a 5 mm contiguous reconstruction algorithm. This specification applies to tumors of the chest, abdomen, and pelvis, while head and neck tumors, and those of the extremities require specific procedures. 6.2.8.2 Chest X-Ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by an aerated lung. However, CT is preferable. 6.2.8.3 Clinical Examination Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, is recommended. Photographs should be retained at the institution. 6.2.8.4 Cytology and Histology Cytologic and histologic techniques can be used to differentiate between complete and partial response in rare cases (e.g., after treatment to differentiate residual benign lesions and residual malignant lesions in germ cell tumors). Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria. 6.2.8.5 Endoscopy and Laparoscopy Endoscopy and laparoscopy have not been fully or widely validated, so their use should be limited to validation studies in specialized institutions, and to confirming complete histopathologic response when biopsy specimens have been obtained. 6.2.8.6 Ultrasound Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules, and for confirming complete disappearance of superficial lesions usually assessed by clinical examination.
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7. Study Parameters 7.1 Therapeutic Parameters For Both Arms A and B 1. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done within 4 weeks prior to randomization. 2. Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks before randomization. 3. All required prestudy chemistries, as outlined in section 3, should be done ≤ 4 weeks before randomization – unless specifically required on Day 1 as per protocol. th Rev. 4/12 NOTE: For Arm A and Arm B, ipilimumab is given on day 1 for cycles 1-4, the induction phase and on day 1 of every 4 cycle (every 12 weeks) in the maintenance phase, starting with cycle 8. Rev. 4/12 Within 4 weeks Within 72 Day 1 of Every Day 1 of Each Day 1 of Every 4th Cycle End of Study Follow 10 11 (28 days) of hours prior to Each 12 Cycle During During Maintenance Assessment Up randomization randomization Cycle weeks Maintenance (1st day of treatment with During for Patients on Ipilimumab) for patients on Test/ Assessment Induction Arm A Arm A and Arm B History and Physical Exam1 X X X X X Height/ Weight X X 2 X 2 X X Vital Signs 3 X X X X X ECOG Performance Status X X X X X Drug Toxicity Assessment X X 4 X 4 X X Pregnancy Test12 X X16 X CBC, differential, Platelets X X4, 5 X14 X4, 5 X Serum Chemistries X X4,6 X4,6 X HIV, Hepatits C antibody X and Hepatitis B angiten Lipase, Amylase X X4 X4 X Research Blood Samples See Section 7.2 CNS imaging (MRI or CT)7 X X 9 X X15
Non-CNS Imaging, 9 15 8 X X X X Including CAP CT Study drug diary X 13 X 13 X
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Rev. 4/12 1. Baseline history and physical should be a complete history and physical, including past medical history performed by a physician. A focused, treatment related exam should be done by the MD or other health professional (licensed nurse practitioner or physician assistant) prior to each study treatment and follow up. 2. Weight should be obtained prior to each study treatment to ensure calculation of the study drug(s) at every cycle. 3. Vitals signs should include blood pressure, heart rate, temperature, respiratory rate and pain level. Vitals signs should be performed before ipilimumab infusion, every 30 minutes during the infusion and one hour after the end of the infusion. 4. Should be performed prior to each infusion or study drug initiation. 5. Hematology labs should include hemoglobin, hematocrit, red blood cell count, white blood cell count, platelets (direct platelet count), as well as total and differential CBC counts. The CBC differential includes enumeration of neutrophils, lymphocytes, eosinophils, monocytes, basophils and any abnormal blood cells. This test should be obtained less than 24 hours prior to the treatment cycle. 6. Serum chemistry analysis should include albumin, urea or BUN, creatinine, ALT, AST, LDH, alkaline phosphatase, Rev. 4/11 direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, CO2, calcium, phosphorus, and uric acid. These labs should be obtained less than 24 hours prior to the treatment cycle. 7. CNS imaging is preferred by MRI however, if an MRI is not clinically indicated, a CT of the head is allowed. 8. Non CNS imaging should include a Chest, abdomen and pelvis CT. Imaging of other sites should be obtained when clinically indicated. 9. If restaging scans indicate partial or complete response, a repeat confirmatory scan should be obtained in 4 weeks (but no sooner than 4 weeks). 10. End of Study Assessment should occur no more than 3 weeks after the discontinuation of study treatment. If the subject had not undergone scans within the past 6 weeks re-imaging is indicated. 11. Every 3 months if patient is < 2 years from study entry. Every 6 months if patient is 2-5 years from study entry. Rev. 4/12 12. For women of childbearing potential, a serum pregnancy test must be obtained and confirmed negative within 72 hours prior to randomization. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the test is positive, the subject must not receive ipilimumab and must not be enrolled in the study. Urine HCG is sufficient before each dose as long as the test has a minimum sensitivity of 25 IU/L.See Section 3.5. 13. GM-CSF study drug diaries should be distributed on cycle 1 day 1 and collected at the beginning of the next cycle. All outstanding diaries should be obtained at the end of study assessment. 14. CBC needs to be obtained (for patients on Arm A only) before starting each series of GM injections on day 1 of each cycle during maintenance therapy. 15. If a patient discontinues treatment for any reason other than progression, scans will be done every 12 weeks until progression.
Rev. 4/11 16. Urine HCG can be done before each cycle or serum pregnancy test if clinically indicated.
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7.2 Biological Sample Submissions 1. Submission of pathology samples for diagnostic review is mandatory in order for the patient to be considered evaluable.
Rev. 12/10, 4/12 2. Blood and post-therapy pathology samples for banking should be submitted as outlined in Sections 10 and 11 per patient consent. NOTE: It is required that biological sample submissions be logged into the ECOG Sample Tracking System (STS) (see Section 11.5) for purposes of monitoring compliance and determination of reimbursement levels. NOTE: An informed consent must be signed prior to the submission of any samples for any laboratory study, including mandatory diagnostic reviews and banking. Samples for banking should be submitted only from patients who have given written consent for the use of their samples for these purposes.
Rev. 4/12 Induction Maintenance Post Phase: Phase: End of Therapy Baseline1 Study Every Six (6) Every Twelve (12) Assessment Weeks2 Weeks6
5 Rev. 12/10 Pathology Samples X4 X
Peripheral Blood Mononuclear Cells X X X X 3 Rev. 12/10 (green top tubes)
Rev. 12/10 Serum (red top tubes)3 X X X X
Rev. 12/10 1. Prior to treatment. 2. Every six weeks or every two cycles. Rev. 12/10 3. At each time point submit one (1) 10 cc red top tube and ten (10) 10 cc green top tubes. Submit from patients who answer “Yes” to I agree to provide additional blood for research. Rev. 12/10 4. MANDATORY: Samples from primary melanoma and subsequent metastatic tumor must be submitted, refer to Section 10.
Rev. 12/10 5. If any biopsies are performed for purposes of patient care, samples are requested to be submitted from patients who answer “Yes” to I agree to provide tissue for research. Rev. 4/12 6. Maintenance blood samples are to be collected at the time of the clinical blood draws: Arm A every four (4) cycles [twelve (12) weeks], Arm B at time of standard of care clinical assessments but no more often than every twelve (12) weeks.
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8. Drug Formulation and Procurement
This information has been prepared by the ECOG Pharmacy and Nursing Committees. Availability Drug Ordering: Bristol-Myers-Squibb is supplying ipilimumab, through the Division of Cancer Treatment and Diagnosis, NCI, for this protocol. Maintenance of NCI drug accountability records is required. Ipilimumab (NSC 732442) may be requested by the Principal Investigator (or their authorized designees) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained-see general information). Completed Clinical Drug Requests (NIH-986) should be submitted to the PMB by fax (301) 480-4612 or mailed to the Pharmaceutical Management Branch, CTEP, DCTDC, NCI, 9000 Rockville Pike, EPN, Rm. 7179, Bethesda, MD 20892. The NCI Clinical Drug Request form is available on the NCI home page (http://ctep.info.nih.gov) or by calling the PMB at (301) 496-5725. NCI Supplied Agent(s) – General Information NOTE: Under no circumstances can commercially supplied Ipilimumab be used or substituted for the NCI-supplied Ipilimumab. Questions about drug orders, transfers, returns, or accountability should be addressed to the PMB by calling (301) 496-5725 Monday through Friday between 8:30 AM and 4:30 PM Eastern Time. Drug Returns: All unused drug supplies must be returned to the PMB. Use the NCI Return Agent Form available on the NCI home page, (http://CTEP.cancer.gov) or call PMB at (301) 496-5725. Rev. 4/11 Drug Accountability: The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, disposition, and return of all drugs received from the PMB using the NCI Investigational Agent Accountability Record available on the NCI home page (http://CTEP.cancer.gov) or by calling the PMB at (301) 496-5725. 8.1 Ipilimumab The investigational product is defined as a pharmaceutical form of an active ingredient being tested as a reference in the study, whether blinded or unblinded. In this study, the investigational product is ipilimumab. 8.1.1 Drug Name Ipilimumab (NSC 732442) Rev. 4/11 8.1.2 Chemical Name or Amino Acid Sequence 4 polypeptide chains, 2 identical heavy chains with 447 amino acids and 2 identical light chains consisting of 215 amino acids. 8.1.3 Other Names Anti-CTLA-4 monoclonal antibody, MDX-010 Rev. 4/11 8.1.4 Classification Human monoclonal antibody M.W.: 147,991 Daltons
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8.1.5 Mode of Action Ipilimumab is specific for the CTLA4 antigen expressed on a subset of activated T- cells. CTLA4 interaction with the B7 molecule, one of its ligands expressed on professional antigen presenting cells, can down-regulate T-cell response. Ipilimumab is thought to act by blocking the interaction of CTLA4 with the B7 ligand, resulting in a blockade of the inhibitory effect of T-cell activation. The CTLA4/B7 creates the interaction.
Rev. 4/11 8.1.6 Description Ipilimumab is a fully human immunoglobulin (IgG1κ) with two manufacturing processes- ongoing trials have been using substances manufactured using Process B. This trial, E1608, uses ipilimumab that is manufactured by Process C. The Process C has been developed using a higher producing sub-clone of the current Master Cell Bank, and modified cell culture and purification steps. Rev. 4/11 8.1.7 How Supplied Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the DCTD/NCI. Ipilimumab is available as a 50 mg/10 mL (5 mg/ mL) and a 200 mg /40 mL (5 mg/mL) single-use vial. The vial is a clear, colorless, sterile, isotonic aqueous solution (pH of 7) that may contain particles. Each vial is a Type I flint glass vial with gray butyl stoppers and sealed with aluminum seals.
Process B Process C Component 50 mg/ viala 200 mg/ vialb 50 mg/ viala 200 mg/ vialb Ipilimumab 53.5 mg 213 mg 53.5 mg 213 mg Sodium Chloride, USP 62.6 mg 249 mg 62.6 mg 249 mg TRIS-hydrochloride 33.7 mg 134.3 mg 33.7 mg 134.3 mg Diethylenetriamine pentacetic acid 0.42 mg 1.67 mg 0.42 mg 1.67 mg Mannitol, USP 107 mg 426 mg 107 mg 426 mg Polysorbate 80 (plant-derived) 1.07 mg 4.26 mg 1.18 mg 4.69 mg Sodium Hydroxide QS to pH 7 Hydrochloric acid QS to pH 7 Water for Injection QS: 10.7 mL QS: 42.6 mL QS: 10.7 mL QS: 42.6 mL Nitrogenc Processing agent
a Includes 0.7 overfill; b Includes 2.6 mL overfill. c Nitrogen is used to transfer the bulk solution through the pre-filled and sterilizing filters into the aseptic area.
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8.1.8 Preparation and Administration Guidelines for Ipilimumab Ipilimumab 10mg/kg IV, Day 1 of each cycle during Induction Therapy (cycles 1-4). During Maintenance Therapy (cycles 5 and higher) ipilimumab 10mg/kg IV, Day 1 of every 4th cycle (12 weeks). Ipilimumab is given undiluted or further diluted in 0.9% NaCl injection, USP or 5% Dextrose injection, USP to a concentration between 1 mg/mL and 4 mg/mL. Ipilimumab is stable in a polyvinyl chloride (PVC), non-PVC/non DEHP (di-(2-ethylhexul) phthalate) IV bag or glass container up to 24 hours refrigerated at (2º to 8º C) or at room temperature/room light. The supplies needed for ipilimumab preparation and administration include calibrated syringes and infusion containers. The product may be infused using a volumetric pump at the protocol-specific dose(s) and rate(s) through a PVC IV solution infusion set with a 0.2 μm or 1.2 μm in-line polyethersulfone or 1.2 μm positively charged nylon filter to complete the infusion in 90 minutes, with a 10mL normal saline flush at the completion of the infusion.
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1. As ipilimumab is stored at refrigerated temperatures (2-8ºC), allow the appropriate number of vials of ipilimumab to stand at room temperature for approximately five minutes. 2. Aseptically withdraw the required volume of ipilimumab solution into a syringe. Insert the needle at an angle into the ipilimumab vial by placing the needle – bevel side down – against the glass, with the tip touching the neck of the vial. The drug vial concentration is 5 mg/mL. [Note: A sufficient excess of ipilimumab is incorporated into each vial to account for withdrawal losses.] 3. Ensure that the ipilimumab solution is clear colorless, essentially free from particulate matter on visual inspection. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall, etc. 4. Inject ipilimumab solution withdrawn into an appropriate size evacuated infusion bag to produce a final infusion volume that has been calculated from the weight of the patient. For example, if preparing a 10mg/kg treatment for a 65 kg patient you will use 3 ½ vials for a total volume of 130 mL. 5. Mix by GENTLY inverting several times. DO NOT shake. 6. Visually inspect the final solution. If the initial diluted solution or final dilution for infusion is not clear or contents appear to contain precipitate, the solution should be discarded. 7. Do not draw into each vial more than once. Any partial vials should be safely discarded and should not be stored for reuse. Ipilimumab should be administered under the supervision of a physician experienced in the use of intravenous (IV) agents. Ipilimumab is administered as an IV infusion only. 8.1.9 Storage, Handling, and Dispensing 8.1.9.1 Storage Ipilimumab must be stored in a secure area according to local regulations. The investigator must ensure that it is stored in accordance with the environmental conditions as determined by BMS and defined in the Investigator Brochure or SmPC/reference label. Ipilimumab must be stored Rev. 4/11 at a temperature ≥ 2°C and ≤ 8°C, protected from light. Do not freeze.. 8.1.9.2 Handling and Disposal As with all injectable drugs, care should be taken when handling and preparing ipilimumab. Whenever possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents applying aseptic technique. Latex gloves are required. If ipilimumab concentrate or solution comes in contact with skin or mucosa, immediately and thoroughly wash with soap and water. After final drug reconciliation, unused ipilimumab solution should be disposed at the site following procedures for the disposal of anticancer drugs. 8.1.9.3 Dispensing It is the responsibility of the investigator to ensure that ipilimumab is only dispensed to study subjects. The ipilimumab must be dispensed only from official study sites by authorized personnel according to local regulations.
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Rev. 4/11 8.1.10 Stability Shelf-life surveillance of the intact vials is ongoing. Undiluted or diluted ipilimumab solution is stable in a polyvinyl chloride (PVC), non-PVC/non DEHP (di-(2-ethylhexul) phthalate) IV bag or glass container up to 24 hours refrigerated at (2º to 8º C) or at room temperature/room light. CAUTION: Ipilimumab does not contain antibacterial preservatives. Use prepared IV solution immediately. Discard partially used vials. 8.1.11 Method of Administration Use a volumetric pump to infuse ipilimumab over 90 minutes via a PVC IV infusion set with a 0.2 micron or 1.2 micron in-line polyethersulfone or 1.2 micron positively charged nylon filter (Note: can also use any of the hospital IV infusion set with 0.2 micron or 1.2- micron filter). Rev. 4/11 8.1.12 Route of Administration Intravenous. Do not administer ipilimumab as an IV push or bolus injection. 8.1.13 Patient Care Implications Monitor patients for immune-related adverse events, e.g., rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism. If you suspect toxicity, refer to the protocol guidelines for ruling out other causes. Ipilimumab may be excreted in milk or cross the placenta; therefore, nursing women and women with known or suspected pregnancy should not take ipilumumab. Closely monitor patients who are on narcotics during the treatment with ipilumumab. Narcotics may mask GI signs and symptoms such as diarrhea or abdominal pain, which are relevant complications of a bowel perforation. Minor diarrhea can be a potential sign of colitis and require immediate attention. 8.1.14 Packaging and Labeling BMS will provide ipilimumab at no cost for this study. Ipilimumab will be provided in open-label containers. The labels will contain the batch number, content, storage conditions, and dispensing instructions along with the Investigational New Drug (IND) caution statement. Ipilimumab will be supplied at a concentration of 5 mg/mL in vials containing 40 mL solution. 8.1.15 Side Effects See Section 5.4. 8.1.16 Ipilimumab Accountability It is the responsibility of the investigator to ensure that a current record of ipilimumab disposition is maintained at each study site where ipilimumab is inventoried and disposed. Records or logs must comply with applicable regulations and guidelines, and should include: • Amount received and placed in storage area. • Amount currently in storage area. • Label ID number or batch number and use date or expiry date. • Dates and initials of person responsible for each ipilimumab inventory entry/movement. • Non-study disposition (e.g., lost, wasted, broken). Please refer to the CTEP guidelines for drug return and destruction at: http://CTEP.cancer.gov
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8.2 GM-CSF 8.2.1 Other Names Granulocyte-macrophage colony stimulating factor, Sargramostim, rHu GM-CSF, Leukine. 8.2.2 Classification Colony stimulating factor; cytokine 8.2.3 Mode of Action Primarily affects the proliferation, differentiation, and activation of granulocytes and macrophages by inducing partially committed progenitor cells. Is also capable of activating mature granulocytes and macrophages. Rev. 4/11 8.2.4 Storage and Stability Lyophilized vials and reconstituted lyophilized GM-CSF solutions must be kept refrigerated between 2-8°C (36-46°F); DO NOT FREEZE. Sterile Water for Injection, USP (without preservative): Lyophilized GM-CSF vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored in the original vial for up to 20 days at 2–8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. 8.2.5 Dose Specifics GM-CSF 250 mcg SQ Q Day, Days 1-14 of each cycle. Rev. 4/11 8.2.6 Preparation Vials of GM-CSF will be reconstituted by a pharmacist or designated site personnel. Due to the length of treatment it is recommended the vials be reconstituted using Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) which may be stored in the original vial for up to 20 days at 2–8°C prior to use. Pharmacist must clearly indicate expiration date of reconstituted solution on the GM-CSF vial or packaging. Lyophilized GM-CSF is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP. Lyophilized GM-CSF (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent. The contents of vials reconstituted with different diluents should not be mixed together. During reconstitution, the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming. Avoid excessive or vigorous agitation. DO NOT SHAKE. When used for subcutaneous injection, GM-CSF should not be diluted further. Vials of reconstituted GM-CSF will be sent home with patients for self- administration. Patients must obtain, or be supplied with, the necessary supplies for self-administration including sterile needles and syringes, alcohol swabs, and a cooler for the transport of the vials. Prior to sending the patient home with the reconstituted GM-CSF a designated site personnel will provide an educational session on how to self-administer the agent, storage of the agent and proper disposal of used syringes and needles. Patients will be instructed to return all unused, partially used, expired or empty containers of GM-CSF back to the site for proper destruction. The site will also provide the patient with Appendix XIV, Self- Administration Guide for GM-CSF.
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8.2.7 Route of Administration GM-CSF will be administered subcutaneously. 8.2.8 Incompatibilities No compatibility information available. Drugs which may potentiate the myleoproliferative effects of sargramostim, such as lithium and corticosteroids, should be used with caution. 8.2.9 Availability Rev. 4/11 GM-CSF is an investigational agent, available free of charge and distributed by Genzyme. GM-CSF is available as a lyophilized, sterile, preservative-free powder (250 mcg) that requires reconstitution with 1 mL sterile water for injection. Initial Drug Orders for Each Patient Rev. 4/11 Following submission of the required documents and patient randomization to Arm A, a supply of GM-CSF may be ordered from Genzyme. Investigators must email a completed E1608 GM-CSF Drug Request Form (See Appendix XII) to Genzyme at [email protected]. No starter supplies are available for this protocol.
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GM-CSF will be shipped to a responsible person (e.g., a pharmacist) at the investigator’s institution. Vials are shipped in validated shippers using ice packs to maintain temperature between 2–8°C. Lyophilized vials must be kept refrigerated between 2–8°C at all times. Quantities must be ordered per cycle, keeping in mind that you will need 14 vials per cycle (1 cycle= 21 days and 250 mcg of GM-CSF is given subcutaneously, once daily for days 1-14 of each cycle. Each vial contains 250 mcg.) A suggested initial shipment is 28 vials (2 cycles). Rev. 4/11 Institutions should allow 3 business days for shipment of drug from Genzyme from receipt of the E1608 Drug Request Form. Shipments will be made from Genzyme on Monday through Thursday for delivery on site Tuesday through Friday. There will be no weekend or holiday delivery of drugs. The E1608 GM-CSF Drug Request Form can be downloaded from the ECOG website in WORD format. Important Reorder Instructions Once it is determined that the patient will continue treatment, please reorder study drug immediately. Institutions should keep in mind the number of vials used per cycle (14 vials per cycle). Rev. 4/11 Institutions should allow 3 business days for shipment of drug from Genzyme from receipt of the E1608 GM-CSF Drug Request Form. Shipments will be made from Genzyme on Monday through Thursday for delivery on site Tuesday through Friday. There will be no weekend or holiday delivery of drugs. The E1608 GM-CSF Drug Request Form can be downloaded from the ECOG website in WORD format. GM-CSF Quality and Complaints Handling Genzyme has requested that the pharmacist or pharmacy designee report any issues related to the quality of GM-CSF to Genzyme Clinical Pharmacy Research Services (CPRS) via fax at 508-424-4484 or 877-237-1292 (toll-free). The company’s CPRS Fax is available for GM-CSF handling and complaint reporting on a 24-hour basis. Complaints are reviewed during normal business hours. Where possible, once a complaint has been logged with CPRSP, the GM-CSF in question should be stored as instructed on the label in a limited access area until otherwise instructed by Genzyme. Questions regarding GM-CSF quality issues can be addressed to CPRS by calling 800-326-7002 or e-mailing [email protected]. Drug Destruction and Return Rev. 4/11 Patients will be instructed to return all unused, partially used, expired or empty containers of GM-CSF to the site for proper destruction. When all patients have completed treatment at your institution, all unused, partially used, expired or empty containers must be destroyed at the site according to the institution’s policy for drug destruction. Please maintain appropriate records of the disposal, including dates and quantities. Sites are required to complete the Certificate of Drug Destruction of Clinical Trials located in Appendix XIII. A copy of this form should be faxed to Genzyme Clinical Pharmacy Research Services (CPRS) at 508-424-4484. Drug Inventory Records Investigational Product Records at Investigational Site(s): It is the responsibility of the Investigator to ensure that a current record of investigational product disposition is maintained at each study site where investigational product is inventoried.
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8.2.10 Drug Information GM-CSF contains 40 mg/mL mannitol, 10 mg/mL sucrose, and 1.2 mg/mL tromethamine. Biologic potency can be expressed in International Units (IU) as tested against the WHO First International Reference Standard. The activity of GM- CSF is estimated to be 5.6 x 106 IU/mg. Refer to the package insert for more information. 8.2.11 Side Effects 1. Most frequently reported: mild to moderate fever, asthenia, chills, headache, nausea, diarrhea, myalgia, bone pain. 2. Body as a whole: fever, chills, malaise, asthenia, abdominal pain, back pain, extremity pain, sepsis, pain. 3. Gastrointestinal: nausea, vomiting, anorexia, diarrhea, stomatitis, GI disorder, GI hemorrhage, liver damage, liver function abnormalities. 4. Musculoskeletal: myalgia, bone pain, arthralgia. 5. Cardiovascular: pericardial effusion, pericarditis, hemorrhage, chest pain, cardiac dysrhythmia, hypotension, heart failure, hypertension. 6. Respiratory: dyspnea, lung disorder, cough, pneumonia, pleural effusion. 7. Dermatologic: rash, urticaria, alopecia, injection site reaction. 8. Neurologic: headache, CNS disorder, dizziness. 9. Metabolic: peripheral edema, edema, hyponatremia. 10. Hematologic: leukocytosis, blood dyscrasia, thrombocytopenia, eosinophilia, splenomegaly. 11. Urologic: abnormal kidney function, urinary tract disorder. 12. Other: vascular leak syndrome (fluid retention, weight gain, edema, polyserositis), first dose effect (fever, facial flushing, hypotension, transient loss of consciousness, headache, tachycardia, and pulmonary dysfunction). 13. Please refer to the package insert for further information. 8.2.12 Nursing/Patient Implications 1. Monitor for central venous catheter occlusion, or generalized thrombosis. 2. Educate patient/support person(s) about rationale for growth factor and potential side effects. 3. Follow protocol guidelines for discontinuing or reducing dose of growth factor following elevated WBC, neutrophil or platelet count. 4. Monitor serum creatinine and liver enzymes, especially in patients with pre- existing renal and/or hepatic dysfunction. 5. Administer antipyretics, antiemetics, and analgesics as ordered/needed: • Acetaminophen can be administered prior to treatment and every 4 hours as needed to decrease/control mild to moderate flu-like symptoms. • Bone pain/myalgia can be managed with analgesics or dose reductions as ordered. 6. Diphenhydramine may be ordered if erythema at subcutaneous injection sites occurs.
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8.2.13 References Anon. American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J. Clin Oncol 1994;12:2471-2508. Grant SM, Heel RC. Recombinant granulocyte-macrophage colony-stimulating factor (rGMCSF): a review of its pharmacological properties and prospective role on the management of myelosuppression. Drugs 1992;43 :516-60. Please refer to the FDA-approved package insert for complete information. Personal correspondence: Kim Murray, Pharm.D., Inimunex Corporation, April 5, 1996. Louie SG. Jung B. Clinical effects of biologic response modifiers. Am J Hosp Pharm 1993;50:(Suppl 3):S10-S18.
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9. Statistical Considerations In this randomized phase II study, patients with advanced melanoma will be randomized to ipilimumab (ipi) or GM-CSF + Ipilimumab using the two stratification factors (AJCC Stage, Prior Therapy). The stratified randomization will be based on the permuted block method. Allowing for one interim analysis described below, a total of 202 eligible patients will be accrued and 149 deaths are expected. To account for the ineligibility rate of 5%, 220 patients will be accrued. Based on previous ECOG accrual of the same patient population, it is expected to complete the accrual in 1.12 years and follow patients for additional 1.5 years. 9.1 Primary Endpoint The primary comparison will be overall survival (OS). It will be an ITT analysis in all eligible patients. It is assumed that the one-year OS rate is 45% in patients treated with ipi and this rate will be improved to 57% in the ipi + GM-CSF arm. If the OS follows an exponential distribution, this difference corresponds to an improvement in the median OS from .87 years to 1.23 years. One interim analysis will be performed at 50% information time (75 deaths). To preserve the overall type I error rate, critical values at the analyses will be determined using the O’Brien and Fleming boundary. Under the accrual and failure rate assumptions above, one interim and final analyses are expected to occur at 1.24 and 2.62 years after activation. The repeated confidence interval of Jennison-Turnbull will also be evaluated at the interim analysis. This design will provide an overall one-sided type I error rate of 0.100 and power of 80%. As a secondary analysis, one-year OS rate will be assessed as described by Korn et al. (JCO, 2008). One-year survival rate adjusted for PS, visceral disease, brain met, and sex will be evaluated. 9.2 Secondary Endpoints In addition the secondary endpoints of progression free survival (PFS), response rate, safety and tolerability will be assessed. PFS is defined as the time from randomization to disease progression or death without progression. For the censored cases, the date of the last disease evaluation date will be used in defining PFS. The utility of immune related response criteria (irRC) will also be evaluated in patients receiving ipilimumab. Standard response criteria (based on the RECIST) will be used in the primary analysis. The immune response will be assessed using the utility of Immune related response criteria (irRC). irRC will be used as secondary and investigational criteria. irRC data will be associated with the RECIST-based clinical response, PFS and OS. The method of Kaplan- Meir will be used to describe PFS and OS in each arm. The Kappa statistics which measures the degree of agreement between the RECIST-based response and irRC will be estimated. McNemar’s test will be used to evaluate the agreement between irRC and RECIST-based clinical response. The landmark analysis will be conducted to evaluate the association between PFS/OS and irRC. Analysis for the secondary endpoints will be mostly descriptive. Toxicity data will be monitored and reviewed carefully. In particular, after 60 patients are treated with ipi or ipi + GM-CSF (approximately 30 in each arm), a detailed review of toxicity data will be performed. Incidence data of specific toxicity type as well overall worst degree toxicity data will be summarized and compared between the two arms. The result of this analysis will be discussed with the ECOG Data Monitoring Committee.
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9.3 Gender and Ethnicity Based on previous data from E3695, E1696, and E1602, the anticipated accrual in subgroups defined by gender and race is:
Ethnic Category Gender Females Males Total Hispanic or Latino 1 0 1 Not Hispanic or Latino 81 138 219 Ethnic Category: Total of all subjects 82 138 220 Racial Category American Indian or Alaskan Native 0 0 0 Asian 1 0 1 Black or African American 2 1 3 Native Hawaiian or other Pacific Islander 0 0 0 White 79 137 216 Racial Category: Total of all subjects 82 138 220 The accrual targets in individual cells are not large enough for definitive subgroup analyses. Therefore, overall accrual to the study will not be extended to meet individual subgroup accrual targets.
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NOTE: ECOG requires that all biological samples submitted be entered and tracked via the online ECOG Sample Tracking System (STS). An STS shipping manifest form must be generated and shipped with the sample submissions. See Section 11.5. Rev. 12/10 10.1 Pathology samples from the primary melanoma and metastases must be submitted for Rev. 4/11 review and classification. If the patient has a history of an unknown primary, submission of samples from metastases will suffice. Submission of pathology samples for diagnostic review is mandatory in order for the patient to be considered evaluable. Pathology review will include evaluation of treatment response and determining pathologic parameters that Rev. 12/10 predict response to treatment. If patient consents to banking, post therapy tumor specimens (if biopsy performed) and tissue leftover from the central review will be stored for future research, including possible genotypic analysis. The submitting pathologist and clinical research associate should refer to Appendix II (Pathology Submission Guidelines) for guidelines and summary of submission requirements. 10.2 Materials Required For This Protocol Rev. 12/10 10.2.1 Forms (MANDATORY) – Send with every pathology submission • ECOG Pathology Material Submission Form (#638 v04.2), Parts A & B completed. Please identify the clinical status of the submitted material (i.e., pretreatment as opposed to remission and relapse). • A copy of the surgical pathology report • Immunologic studies, if available
Rev. 4/12 • Sample Tracking System Shipping Manifest Form (see Section 11.5) In addition to the surgical pathology report, if immunologic studies have been performed at the home institution, it is necessary that these be forwarded as well. Rev. 12/10 10.2.2 Pathology Submissions Rev. 12/10 10.2.2.1 Baseline (MANDATORY) Rev. 4/11 • Paraffin block from primary tumor of melanoma • Subsequent tumor metastases Rev. 4/11 NOTE: Cytology from fine needle aspiration for documenting metastases from known primary is acceptable. If history of multiple primaries, an effort is to be made to submit diagnostic materials from each. If history of unknown primary, submission of metastases will suffice. 10.2.2.2 Post Therapy Rev. 12/10 If available, submit from patients who answer “Yes” to I agree to provide tissue for research. • Paraffin block from post therapy tumor Rev. 4/12 NOTE: If blocks cannot be submitted, please send one (1) H&E and twenty (20) unstained sections from the thickest portion of the tumor. 10.3 Shipping Procedures Log the samples into the ECOG Sample Tracking System (STS) the day of shipment. If the STS is unavailable, an ECOG Generic Specimen Submission Form (#2981) must be submitted with the samples. Once STS is available, retroactively log the shipment into STS, using the actual collection and shipping dates.
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10.3.1 Submission Schedule 10.3.1.1 The required primary and metastatic tumor samples must be submitted within one month of patient registration. 10.3.1.2 Post therapy tumor samples are to be submitted within one month of collection.
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10.3.2 Shipping Address ECOG Pathology Coordinating Office Robert H. Lurie Comprehensive Cancer Center of Northwestern University Medical School Olson Pavilion - Room 8421 710 North Fairbanks Court Chicago, IL 60611 Tel: (312) 503-3384 FAX: (312) 503-3385 An STS shipping manifest form must be generated and shipped with all sample submissions. 10.3.3 Pathology Coordinating Office: Sample Processing and Routing Pathology samples will be forwarded to Dr. Uma Rao for review. NOTE: A copy of the completed submission form will be sent to the Coordinating Center by the Pathology Coordinating Office. 10.4 Banking Rev. 4/12 The residuals and/or derivatives of the blocks/slides submitted will be retained at the ECOG Central Repository for possible use in future ECOG approved studies. Any residual blocks will be available for purposes of individual patient management care on specific written request. If future use is denied or withdrawn by the patient, the samples will be removed from consideration for use in any future study.
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11. Correlative Studies
NOTE: ECOG requires that all biological samples submitted be entered and tracked via the online ECOG Sample Tracking System. An STS shipping manifest form must be generated and shipped with the sample submissions. See Section 11.5. Rev. 12/10 Rev. 12/10 11.1 Blood samples are being collected for possible future use studies, including immune cell numbers and subsets, phenotypic measurements, and functional studies. Submit from patients who answer “Yes” to I agree to provide additional blood for research. 11.1.1 Sample Submission Schedule Serum and peripheral blood mononuclear cells (PBMC) should be collected at: • Baseline (prior to treatment) • Induction Phase: Every six (6) weeks (or every two cycles)
Rev. 4/12 • Maintenance Phase: Every twelve (12) weeks [Arm A: every four (4) cycles, Arm B: at time of routine clinical assessments but no more often than every twelve (12) weeks]. • End of study assessment Rev. 4/12 Questions are to be directed to the Immunological Monitoring and Cellular Products
laboratory (IMCPL) ECOG study coordinator at (412) 624-0078. 11.1.2 Sample Preparation Guidelines 11.1.2.1 Shipping Kits
Rev. 4/12 Specimen shipping kits must be requested from the IMCPL. Please fax the request using the Shipping Kit Request Facsimilie Form (Appendix IX) to (412) 623-6625 or call the IMCPL at (412) 624-0078. Please allow ten days for shipment and provide the following information: • Study Number • Participating Site Number • Contact Person and Telephone Number The kits will be shipped via UPS. Please plan ahead, priority overnight shipment is not possible. Rev. 4/12 Blood samples are to be stored at ambient temperature and shipped the day of collection using the shipping kit. If this is not possible, the red top tubes should be stored overnight at 4oC and the green top tubes stored at room temperature and shipped the next day. Follow shipping instructions provided in the kit carefully. The shipping kit consists of the following: • Insulated shipping container and packing material • Specimen Requisition Form • Air Bill for Federal Express Delivery Service • Shipping Instructions Rev. 4/12 • Shipping Kit Request Form
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11.1.2.2 Sample Submissions Rev. 4/12 At EACH time point please submit the following for both serum and PBMC: • One (1) 10 cc RED top tube
• Ten (10) 10 cc GREEN top tubes Please completely fill all blood tubes as full as possible and collect the correct number and tube type as outlined below: • Ten (10) 10mL green top sodium heparin tubes BD cat #367874 and one (1) 10mL red top serum tube BD cat #367820 (please no gel or serum separators). Each tube must be clearly labeled to include: • ECOG protocol number E1608 • ECOG five-digit patient sequence number • Patient initials • Originating institution/investigator name • Date and time drawn • Collection time point 11.1.2.3 Shipping Procedures Log the samples into the ECOG STS the day of shipment. If the STS is unavailable, an ECOG Generic Specimen Submission Form (#2981) must be submitted with the samples. Once STS is available, retroactively log the shipment into STS, using the actual collection and shipping dates. Rev. 4/12 If the STS is unavailable, notify the IMCPL ECOG study coordinator by fax (412-624-0078) using the Specimen Shipment/Requisition Form (Appendix IX). If you are unable to get through to the laboratory by fax, telephone the ECOG study coordinator at (412) 624-0078 and provide the tracking number. Blood collected into the appropriate tubes should be sealed, wrapped and placed in the specimen shipper kit and shipped at ambient room temperature (not wet or dry ice) on the same day they are drawn by Federal Express overnight courier using the air bill provided in the kit. Shipments must be timed to arrive during normal working hours. The laboratory will be open Monday through Friday to receive samples. Do NOT ship on Fridays or Saturdays, or the day before a legal holiday. Ship by overnight courier Monday - Thursday only to: Immunologic Monitoring and Cellular Products Laboratory University of Pittsburgh Cancer Institute UPCI-IMCPL, Suite 1.2 ECOG Study Coordinator Hillman Cancer Center 5117 Centre Avenue Pittsburgh, PA 15213 Tel: (412) 624-0078 FAX: (412) 623-6625 An STS shipping manifest form must be generated and shipped with all sample submissions. Rev. 4/12 NOTE: Blood samples should NOT be collected on Fridays.
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11.2 Banking Blood samples collected will be retained at the UPCI-IMCPL for use in future ECOG approved studies. If future use is denied or withdrawn by the patient, the samples will be removed from consideration for use in any future study. 11.3 Sample Inventory Submission Guidelines Rev. 4/12 Inventories of all specimens collected and aliquoted will be submitted electronically by secure web application to the ECOG Coordinating Center on a monthly basis or upon request by any laboratory holding and/or using specimens associated with this study.
11.4 Lab Data Transfer Guidelines Rev. 4/12 The data collected or generated on the above mentioned laboratory studies will be submitted electronically via secure data portal to the ECOG Coordinating Center on a quarterly basis. The quarterly cut-off dates are March 31, June 30, September 30, and December 31. 11.5 ECOG Sample Tracking System It is required (barring special circumstances) that all samples submitted on this trial be entered and tracked using the ECOG Sample Tracking System (STS). The software will allow the use of either 1) an ECOG user-name and password previously assigned (for those already using STS), or 2) a CTSU username and password. When you are ready to log the collection and/or shipment of the samples required for this study, please access the Sample Tracking System software by clicking https://webapps.ecog.org/Tst Important: Any case reimbursements associated with sample submissions may not be captured if samples are not logged into STS. Additionally, please note that the STS software creates pop-up windows, so you will need to enable pop-ups within your web browser while using the software. A user manual and interactive demo are available by clicking this link: http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize yourself with the software prior to using the system. Rev. 4/12 A shipping manifest form must be generated and shipped with all sample submissions. Please direct your questions or comments pertaining to the STS to [email protected]. 11.5.1 Study Specific Notes An ECOG Generic Specimen Submission Form (#2981) will be required only if STS is unavailable at time of sample submission. Indicate the appropriate Lab ID # on the submission form: • 0001 = ECOG Pathology Coordinating Office • 0009 = ECOG Immunologic Monitoring and Cellular Products Laboratory Retroactively enter all collection and shipping information when STS is available.
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12. Records to Be Kept
Please refer to the E1608 Forms Packet for the forms submission schedule and copies of all forms. The E1608 Forms Packet may be downloaded by accessing the ECOG World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the ECOG Coordinating Center, FSTRF, 900 Commonwealth Avenue, Boston, MA 02215 (ATTN: DATA). This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly from the ECOG Coordinating Center to CTEP by electronic means. 12.1 Records Retention FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-related documentation, including source documents, long enough to allow the sponsor to use the data to support marketing applications. This study will be conducted under an IND. All records pertaining to the trial (including source documents) must be maintained for: • two years after the FDA approves the marketing application, or • two years after the FDA disapproves the application for the indication being studied, or • two years after the FDA is notified by the sponsor of the discontinuation of trials and that an application will not be submitted. Please contact the ECOG Coordinating Center prior to destroying any source documents.
13. Patient Consent and Peer Judgment
Current FDA, NCI, state, federal and institutional regulations concerning informed consent will be followed.
14. References
1. van Elsas A et al. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induce rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp med. 1999. 190:p.355-66. 2. Hodi FS et al. Biologic activity of CTLA-4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U.S.A. 2003;100:4712-4717. 3. Hodi FS et al. Immunologic and Clinical Effects of Antibody Blockade of Cytotoxic T Lymphocyte-Associated Antigen 4 in Previously Vaccinated Cancer Patients. Proc Natl Acad Sci USA. 2008; 105 (8): 3005-3010. 4. Fong L et al. Combination immunotherapy with GM-CSF and CTLA-4 blockade for hormone refractory prostate cancer: Balancing the expansion of activated effector and regulatory cells. Journal of Clinical Oncology 2007. ASCO Annual Meeting Proceedings Part 1 25:18S. 5. Fong L et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 2009. 69(2):609-15. 6. Hodi FS et al. Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody. Proceedings of ASCO 2008, Abstract 3008, p. 165.
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7. Lenschow D.J., et al., CD28/B7 system of T cell costimulation. Ann Rev Immunol, 1996. 14: p. 233-58. 8. Schwartz R.H. Costimulation of T lymphoctyes: the role of CD28, CTLA4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell, 1992. 71(7): p. 1065-8. 9. Chen L.S., et al., Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell, 1992. 71(7): p. 1093-102. 10. Townsend S.E., et al., Tumor rejection after direct costimulation of CD8+ T cells by B7- transfected melanoma cells. Science, 1993. 259(5093): p. 368-70. 11. Townsend S.E., et al., Specificity and longevity of antitumor immune responses induced by B7-transfected tumors. Cancer Res, 1994. 54(24): p.6477-83. 12. Allison J.P., et al., Manipulation of costimulatory signals to enhance antitumor t cell responses. Curr Opin Immunol, 1995. 7(5): p. 682-6. 13. Linsley P.S., et al., CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med, 1991. 174(3): p. 561-9. 14. Thompson C.B., and Allison J.P. The emerging role of CTLA-4 as an immune attenuator. Immunity, 1997. 7(4): p.445-50. 15. Walunas T.L., et al., CTLA-4 can function as a negative regulator of T cell activation. Immunity, 1994. 1(5): p. 405-13. 16. Kearney E.R., et al., Antigen-dependent clonal expansion of a trace population of antigen- specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J Immunol, 1995. 155(3): p. 1032-6. 17. Krummel M.F. and Allison J.P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995; 182(2): p. 459-65. 18. Krummel M.F., et al., Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo. Int Immunol, 1996. 8(4): p. 519-23. 19. Tivol E.A., et al., Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity, 1995. 3(5): p. 541-7. 20. Waterhouse P. et al., Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science, 1995. 270(5238): p. 985-8. 21. Chambers C.A., et al., Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity, 1997, 7(6): p. 885-95. 22. CA184022 Clinical Study Report. A Randomized, Double-Blind, Multi-center, Phase II Fixed Dose Study of Multiple Doses of Ipilimumab (MDX-010) Monotherapy in Patients with Previously Treated Unresectable Stage III or IV Melanoma. Bristol-Myers Squibb Company and Medarex Inc, 2008. Document Control No. 930026869. 23. CA184008 Clinical Study Report. A Multicenter, Single Arm Phase 2 Study of MDX-010 (BMS 734016) Monotherapy in Patients with Previously Treated Unresectable Stage III or IV Melanoma. Bristol-Myers Squibb Company and Medarex Inc, 2008. Document Control No. 930025464. 24. CA184007 Clinical Study Report. Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Comparing the Safety of Ipilimumab Administered With or Without Prophylactic Oral Budesonide (Entocort EC) in Patients with Unresectable Stage III or IV Malignant Melanoma. Bristol-Myers Squibb Company and Medarex Inc, 2008. Document Control No. 930026874.
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25. Korn EL, Liu P-Y, Lee S, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26:527-534. 26. Chapman PB, Einhorn E, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, et al. Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in Patients with Metastatic Melanoma. J Clin Oncol. 1999;17(9)2745-2751. 27. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, et al. Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma. J Clin Oncol. 2000;18:158-166. 28. Bedekian AY, Millward, M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, et al. Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: the Olimersen Melanoma Study. J Clin Oncol. 2006:24:4738 4745.
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Version Date: February 24, 2012
Appendix I
Informed Consent Template for Cancer Treatment Trials (English Language)
This is a clinical trial, which is a type of research study. Your doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your doctor for more explanation.
You are being asked to take part in this study because you have been diagnosed with a type of cancer called malignant melanoma which spread beyond the local area and cannot be surgically removed.
WHY IS THIS STUDY BEING DONE?
Rev. 4/12 The purpose of this study is to test the safety of giving both ipilimumab and GM-CSF at the same time compared to just ipilimumab alone. We would also like to find out what effects, good and bad that this combination of drugs may have on your cancer. Ipilimumab was approved by the FDA for use by itself as treatment for melanoma. However, in this study, the dose and treatment schedule of ipilimumab, as well as its use in combination with GM-CSF, is different from what was approved by the FDA, so it is considered an investigational treatment. GM-CSF is considered to be investigational and is not approved for use with your type of cancer.
Ipilimumab is an antibody that acts against a molecule called Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) that controls a part of your immune system by shutting it down. An antibody is a common type of blood protein. Your immune system (a system that defends your body against potentially harmful agents) uses antibodies to find and destroy harmful agents such as bacteria and viruses, which may cause sickness and disease. Antibodies can also be produced in the laboratory for treating patients. There are now several approved antibodies for treating cancer and other diseases.
Researchers think that one way cancers grow is by escaping the immune system. An antibody against CTLA-4 can prevent CTLA-4 from shutting down the immune system for a time. It is believed that this may help your body destroy cancer cells by allowing your immune system to continue fighting them. In laboratory studies, it has been possible to get rid of some cancers by using an antibody that acts against CTLA-4.
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GM-CSF is a protein that your body normally produces to signal to your body to make white blood cells. White blood cells are very important in the body’s defense system as they help identify and destroy foreign invaders, such as bacteria, viruses, and cells that don’t belong, such as cancer cells. Injections of GM-CSF increase your body’s production of white blood cells and also help enhance the function of the white blood cells.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
About 220 people will take part in this study. Of the total amount who will participate in the study, half will receive both ipilimumab and GM-CSF. The other half will receive ipilimumab alone.
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
BEFORE YOU BEGIN THE STUDY You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests, or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your doctor. • A medical history (questions about your health, current medications, and any allergies). • A physical exam. The research doctor or another research healthcare professional will complete a physical assessment, including blood pressure, pulse, rate of breathing, temperature, and height and weight. • An assessment of your tumor by CT (Computerized Tomography, also known as a CAT scan. A CT scan is a very detailed x-ray exam.) Scans of your chest, abdomen, and pelvis must be performed within 28 days of starting study treatment, and an MRI (Magnetic Resonance Imaging) of your brain must be performed within 28 days of starting study treatment. • Blood tests. Blood (about 2 tablespoons), will be taken from a vein in your arm to check blood cell counts, how well your organs are functioning, and to test for any infections. • Blood test for pregnancy, if you are a woman of child-bearing potential. (This test must be collected within 3 days of study assignment.) Approximately one teaspoon of blood or less will be drawn for this test. • Additional blood tests to check if you are infected by HIV, a virus that causes damage to your immune system and Hepatitis, a virus that causes damage to your liver.
If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in this research study.
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DURING THE STUDY
You will be "randomized" into one of the study groups described below. Randomization means that you are put into a group by chance. A computer program will place you in one of the study groups. Neither you nor your doctor can choose the group you will be in. You will have an equal chance of being placed in any group.
If you are in group 1 (called "Arm A")
Induction Phase: Weeks 1 through 12/Cycles 1-4
If you take part in this research study, you will receive the study drug ipilimumab by an infusion into a vein (I.V.) or central line (port-a-cath) at weeks 1, 4, 7, and 10 (cycles 1, 2, 3, and 4, where each cycle equals 21 days) for a total of four infusions. The infusion time is roughly 90 minutes in length. The infusion will occur at an outpatient facility. You will have your vital signs measured prior to the infusion, and every 30 minutes during the infusion process. One hour after the infusion has stopped, your vital signs will be measured one more time. Thus, the whole infusion process takes about 2 ½ to 3 hours.
You will also be asked to self inject GM-CSF daily for days 1 through 14 of each 21 day cycle. On days 15 through 21, you will NOT have to take any GM-CSF. You will be provided with education and instruction on how to self inject the medications.
Physical Exams: During all treatment cycles, you will have a physical exam, including measuring your weight. You will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking.
Please tell your doctor about any medical treatments that you will have to get during the study (such as elective surgery).
Blood Tests: Every 3 weeks (every cycle), you will undergo blood tests to closely follow you while you are receiving the study drug. These tests will check blood cell counts and how well your organs are functioning. These tests will be done more often than if you were not on this study. Approximately 4-6 tablespoons of blood will be needed at each visit.
Study Diary: You will be asked to record the daily doses of GM-CSF you self inject in a diary. You will also be asked to record any missed or skipped doses. The diary should capture the date, dose, and time of the drug administration, including side effects such as irritation at the injection site or pain and swelling.
Assessment of your cancer: by CT (Computerized Tomography) of your chest, abdomen, and pelvis and an MRI (Magnetic Resonance Imaging) of your brain. These assessments will be performed every 12 weeks. If your disease is found to be improving, you will be asked to repeat the CT and MRI scans in about 4 weeks.
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Maintenance Phase If your disease remains stable or continues to improve, you may receive additional doses of ipilimumab every 3 months after the last dose you received at week 10. Prior to receiving the doses you will be asked to undergo the following: • Physical Exam (weight and vital signs) and questions about your current health, including any changes in your symptoms and any medications you are taking. • Routine blood tests (about 4-6 tablespoons) to check your blood cell counts, how your organs are functioning, and any effects the drug may have on your blood. You will also be asked to take a pregnancy test if you are a woman of child bearing potential. During the maintenance phase, you will continue to self inject GM-CSF for the first 14 days of every 21 day cycle. You will also continue to undergo restaging scans to evaluate the extent of your disease every 12 weeks. Experience with the drug ipilimumab has shown that for some patients, their disease may get larger before it stabilizes or gets smaller. If your disease is getting larger, we may continue to follow and treat your disease at the discretion of you and your doctor.
If you are in group 2 (called "Arm B")
Induction Phase: Weeks 1 through 12/Cycles 1-4
If you take part in this research study, you will receive the study drug ipilimumab by an infusion into a vein (I.V.) or central line (port-a-cath) at weeks 1, 4, 7, and 10 (cycles 1, 2, 3, and 4, where each cycle equals 21 days) for a total of four infusions. The infusion time is roughly 90 minutes in length. The infusion will occur at an outpatient facility. You will have your vital signs measured prior to the infusion, and every 30 minutes during the infusion process. One hour after the infusion has stopped, your vital signs will be measured one more time. Thus, the whole infusion process takes about 2 ½ to 3 hours.
Physical Exams: During all treatment cycles, you will have a physical exam, including measuring your weight. You will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking.
Please tell your doctor about any medical treatments that you will have to get during the study (such as elective surgery).
Blood Tests: Every 3 weeks (every cycle) you will undergo blood tests to closely follow you while you are receiving the study drug. These tests will check blood cell counts and how well your organs are functioning. These tests will be done more often than if you were not on this study. Approximately 4-6 tablespoons of blood will be needed at each visit.
Assessment of your cancer: by CT (Computerized Tomography) of your chest, abdomen, and pelvis and an MRI (Magnetic Resonance Imaging) of your brain. These assessments will be performed every 12 weeks. If your disease is found to be improving, you will be asked to repeat the CT and MRI scans in about 4 weeks.
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• Physical Exam (weight and vital signs) and questions about your current health, including any changes in your symptoms and any medications you are taking. • Routine blood tests (about 4-6 tablespoons) to check your blood cell counts, how your organs are functioning, and any effects the drug may have on your blood. You will also be asked to take a pregnancy test if you are a woman of child bearing potential. You will continue to undergo restaging scans to evaluate the extent of your disease every 12 weeks. Experience with the drug ipilimumab has shown that for some patients, their disease may get larger before it stabilizes or gets smaller. In this situation, we will continue to follow and treat your disease at the discretion of you and your doctor.
WHEN I AM FINISHED WITH TREATMENT You will be asked to return to the clinic within 21 days following the last dose of ipilimumab or GM- CSF. The following tests/exams will be performed:
• Physical Exam (weight and vital signs) and questions about your current health, including any changes in your symptoms and any medications you are taking. • Routine blood tests (about 4-6 tablespoons) to check your blood cell counts, how your organs are functioning, and any effects the drug may have on your blood. You will also be asked to take a pregnancy test if you are a woman of child bearing potential. • A CT and MRI if you have not had one in the last 6 weeks.
Rev. 4/11, After you are finished taking all study-related treatment, the study doctor will ask you to visit the 4/12 office for follow-up exams to keep track of your medical condition every 3 months (if within 2 years of study registration) and every 6 months (if within 2-5 years of study registration). You might receive follow-up phone calls if you cannot come in for an office visit. We would like to keep track of your medical condition for 5 years from study entry.
Central Review
Rev. 12/10 Samples from your primary and metastatic tumor will be sent to a central laboratory to be examined by a central reviewer. This review will be used to confirm the results of the local institutional review.
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STUDY CHART
In this study, a period of 21 days is known as a cycle. You will receive ipilimumab once every 21 days for 4 cycles and GM-CSF daily for 14 days of the 21 days each cycle if you are on Arm A and ipilimumab once every 21 days for 4 cycles if you are on Arm B. After 4 cycles of ipilimumab, you only then receive it once every 3 months. The cycle will be repeated until you stop participating in the study. Each cycle is numbered in order. Research Study Chart or Plan
Study Phase Study Week Procedures
Screening Up to four weeks (28 Read and sign informed consent, physical exam, vital signs, days) before first infusion review of medications, blood samples, blood samples for infectious diseases, review of overall health status, medical history. MRI of brain and CT of chest, abdomen, and pelvis. Screening Within 72 hours of first Pregnancy test, blood samples infusion Induction Phase Day 1 of cycles 1, 2, 3, Physical exam, vital signs, review of medications and and 4 medication log, blood samples, ipilimumab infusion, review of overall health status Induction Phase Week 12 Repeat CT scans and brain MRI Maintenance Day 1 of cycles 5 and Blood samples Phase, ARM A higher (until the end of ONLY study treatment) before starting GM-CSF injections Maintenance Phase Every 12 weeks after the Scans will continue to be repeated every 12 weeks. If they cycle 4 (week 12) infusion show that the cancer is worsening, you will come off study. If your cancer is found to be improving, then you will be asked to undergo a repeat scan no sooner than 4 weeks later to confirm the result. Physical exam, vital signs, review of medications and medication log, blood samples, infusion of ipilimumab. End of Study After last dose of study Physical exam, vital signs, blood samples, CT and MRI (if not Assessment drug(s) performed within 6 weeks), review of medications and medication log and review of overall health status Rev. 4/11. Follow Up After completion of all Office visits to keep track of your medical condition every 3 4/12 study treatment months (if within 2 years of study registration) and every 6 months (if within 2-5 years of study registration). You might also receive follow up phone calls.
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STUDY PLAN Another way to find out what will happen to you during the study is to read the chart below. Start reading at the top and read down the list, following the lines and arrows.
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HOW LONG WILL I BE IN THE STUDY?
You will be in this research study for at least 24 weeks and possibly for a year or more. If you experience serious side effects however, you may be taken off the study before the 24 week point is reached.
The research doctor may decide to take you off the research study for many reasons including if: • It is considered to be in your best interest • The study treatment or procedures are found to be unsafe or ineffective • There is any problem with following study treatments and procedures • Your condition worsens • Other unforeseen reasons
If you are removed from the research study, the research doctor will explain to you why you were removed. If you are removed, you will be asked to participate in the follow up phase of Rev. 4/11 the study.
In addition, you can stop participating in the research study at any time. If you decide to stop participating in this research study, we encourage you to talk to your research doctor about how to do so safely.
Rev. 4/11
CAN I STOP BEING IN THE STUDY?
Yes. You can decide to stop at any time. Tell the doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely.
It is important to tell the doctor if you are thinking about stopping so any risks from the study drugs can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you.
The doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest, if you do not follow the study rules, or if the study is stopped.
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WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking the study drugs. In some cases, side effects can be serious, long lasting, or may never go away. There is also the risk of death. You should talk to your doctor about any side effects that you have while taking part in the study. Non immune-based Risks Associated with Ipilimumab: While receiving treatment with ipilimumab, you may be at risk of side effects that occur during or shortly after the infusion (within 24 hours), or later after the infusion has finished. In isolated cases, some ipilimumab-related side effects may occur many months after the last dose of ipilimumab. Likely: • Diarrhea • Nausea or the urge to vomit • Fatigue or tiredness Less Likely: • Abnormally fast irregular heartbeat • Belly pain • Constipation • Vomiting • Chills • Fever • Lowered white blood cell count (may make you more likely to get infections) • Loss of appetite • Dehydration (when your body does not have as much water and fluid as it should) • Joint pain • Abnormal function of the nerve that controls facial expression • Headache or head pain • Sudden or traumatic injury to the kidney • Itching • Hives • Low blood pressure Rare but Serious: • Partial or complete blockage of the small and/or large bowel.
Rev. 10/11 •
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Immune-Based Events Considered to be Related to Ipilimumab There are side effects that may also occur that are called immune-based events (where your immune system attacks your normal cells). The majority of the side effects seen so far have not been serious; however almost 50% of all participants receiving ipilimumab have experienced an immune-based event. Serious events are side effects which are fatal or life threatening; require you to be hospitalized; may permanently disable you or make you weak and unable to function at your current level; or may jeopardize you or require surgery or intervention by your doctor. These immune-based side effects have usually been controlled by stopping ipilimumab treatment and if needed, with medications, including steroids (medications that are used to decrease inflammation). If you develop an immune-based event, the symptoms may take several months to improve. Immune-based side effects observed in previous Ipilimumab research studies include: • Esophagus/Stomach/Intestine: The most common stomach/intestinal event is diarrhea, which has occurred in about 10% of participants taking ipilimumab. Diarrhea due to ipilimumab ranges from mild to very severe with bleeding and may be life threatening. Some cases of diarrhea have started out as mild and then become severe. About 1% of participants have had diarrhea or stomach/intestinal complications that required surgical removal of part of their intestine or resulted in death. All other cases of diarrhea have been successfully treated by either stopping ipilimumab and/or treatment with anti-diarrhea medicine or with steroids. About 10% of participants treated with ipilimumab have also developed abdominal pain either alone or in combination with diarrhea. Rarely, constipation may be associated with ipilimumab. You should tell your doctor if you develop any diarrhea, constipation, any change in your bowel movements, have blood in your stool, or have abdominal pain. Your doctor may want to perform tests to better understand why you have these symptoms. These tests will allow your doctor to look at your intestine for damage. It may also help determine the type of treatment you might need, which may include the use of steroids. You may have to go into the hospital for doctors to investigate and treat the diarrhea or other stomach/intestinal symptoms. Also, there can be Inflammation of the esophagus (gullet or the tube that goes from mouth to stomach through which food passes) that can make swallowing difficult or painful.
Rev. 10/11 In addition, ipilimumab may increase your chance of bowel perforation. A bowel perforation means that your bowel, small or large, has developed a hole which allows the contents of your intestine to leak into the abdomen. This is considered a medical emergency as it causes a severe infection which can result in death. It has also been reported that patients with bowel metastasis of melanoma (melanoma cancer which has spread to the bowel) might be at higher risk of bowel perforation (tear), which could also result in death. If you know you have diverticulum (protrusion of soft tissue through the colonic wall) and/or diverticulitis (inflammation in the diverticulum), you need to tell your doctor and your doctor will evaluate whether it is appropriate to treat you with ipilimumab.
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Rev. 10/11 • Skin: Rash is a common immune-based event in participants treated with ipilimumab. Rash has occurred in about 20% of participants; most cases have been mild and less than 1% of cases have been serious. Some participants have had itching alone or together with the rash. There can also be Inflammation or damage to the tissue where a drug was injected.
Rev. 10/11 A condition where the skin loses pigment and turns white (vitiligo), has occurred in less than 5% of participants. This condition is likely to be irreversible and permanent. A condition in which blistering and peeling of the top layer of the skin occurs and resembles a severe burn have been rarely reported. It can be very severe and may result in death. • The eye: In rare cases, administration of ipilimumab has been associated with inflammation in the various parts of the eye or with pigment (color) changes in the retina. There have been no known cases of permanent eye damage but these conditions could potentially interfere with your eyesight or even cause blindness if untreated. If these conditions develop, they may require treatment to reduce inflammation. In rare cases, double vision occurred as a result of muscle weakness. You should immediately tell your doctor if you think there is a change in your eyesight, if you develop double vision, or if you develop eye pain while you are on this study. • Pancreas: Inflammation of the pancreas is called pancreatitis. Pancreatitis can occur suddenly (called “acute”) or it can occur slowly over time (called “chronic”). Symptoms of pancreatitis usually include abdominal pain, nausea, vomiting, and fever. Your pancreas is responsible for producing digestive enzymes which help the body digest food as well as producing insulin which helps maintain your blood sugar levels. Mild acute pancreatitis usually doesn’t permanently affect digestion or blood sugar levels, although a single severe attack can damage your pancreas and trigger chronic pancreatitis, which destroys the cells that produce both enzymes and insulin. Ongoing damage to enzyme-producing tissue in chronic pancreatitis leads to poor absorption (malabsorption) of nutrients, especially fats; to weight loss; and to oily, malodorous stools. Damage to or destruction of insulin producing cells means blood sugar isn’t metabolized properly, often leading to diabetes. Rev. 10/11 • Endocrine glands: Rarely (approximately 2%), participants have developed problems with particular glands (a gland is a group of cells or an organ that secretes a hormonal substance) such as the pituitary gland, the thyroid, the adrenal gland, or the testes. Symptoms that may be associated with problems of the pituitary or adrenal glands include fatigue, confusion, weight loss, inability to perform sexually (impotence), and headache. • Liver: Approximately 4% of participants have developed serious problems with the liver as a result of ipilimumab treatment. Inflammation of the liver due to ipilimumab can range from mild to severe, and in very few cases, it can be life threatening. However, most severe cases have been successfully treated by stopping ipilimumab treatment and by administering anti-inflammatory medications such as steroids. You should contact your doctor if you experience symptoms that may be associated with problems of the liver that include fatigue, weakness, vomiting, nausea, and abdominal pain. More frequent blood draws and a liver biopsy may be required if you develop serious liver abnormalities.
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• Other organs: Rarely, participants have developed problems with the liver, kidney (proteinuria which is extra protein in urine), heart, muscles, blood vessels, and lung while taking ipilimumab. Acute failure resulting in death has occurred in less than 1% of participants. Symptoms that may be associated with problems of the liver include fatigue, weakness, vomiting, nausea, and abdominal pain. A liver biopsy may be required if you develop serious liver abnormalities. Too much bile in the blood causing a yellow color to the skin, gums, eye, and other tissues (jaundice) could occur. Rev. 10/11 Progressive failure of blood clotting and risk of bleeding is a rare but serious complication of ipilimumab. • Meningitis (inflammation of the membrane surrounding the spinal cord and brain) has developed in less than 1% of participants treated with ipilimumab. This can cause headache, nausea and vomiting, stiff neck, and sensitivity of your eyes to light. • In very rare cases, immune-related motor neuropathy (inflammation of the nerves that control muscles) such as Guillain-Barre Syndrome may occur, which could be life- threatening if not treated appropriately. You should tell your doctor if you experience weakness of your limbs with or without numbness or tingling. In addition, there can be progressive weakness caused by the body’s immune system attacking the skeletal muscles (myasthenia gravis) • Nephritis (inflammation of the kidneys) has developed in less than 1% of participants treated with ipilimumab. The cases of meningitis and nephritis resolved with treatment.
Rev. 10/11 •
• You should tell your doctor immediately if you think you are developing any unusual side effects even if they weren’t listed here or any of the side effects or symptoms listed. • Over-the-counter (OTC) drugs may cause major side effects. Acetominophen and NSAIDS found in most common OTC products for cold, headaches, muscle aches, and fever are safe and effective when used correctly, but too much can damage the liver. Be cautious when using OTC products. If you choose to take an OTC product, inform the nursing staff or your doctor about the drug. In addition, immune-based reactions of any other organs, such as the joints or heart, could also occur. This could cause pain and swelling. Joint pain has been reported by less than 1% of participants receiving ipilimumab. Inflammation of the heart or carditis may occur in all aspects of the heart and symptoms may include shortness of breath, fatigue, and chest pain. Treatment of the inflammation depends on the aspect of the heart which is affected. It may lead to decreased functioning of the heart. Rev. 10/11 • Infusion related reaction: Reaction that can occur during or following the infusion of ipilimumab includes fever, chills, rash, low blood pressure, and difficulty breathing. This occurs in fewer than 20% of all individuals treated with ipilimumab.
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Risks Associated with GM-CSF Likely • Fever • Chills • Fatigue • Nausea • Pain, swelling, and redness at injection site • Bone pain • Loss of appetite • Headache • Muscle and joint pain • Abdominal pain • Back pain • Rash • Itching
Less Likely • Elevation of liver function tests (found through bloodwork) • Vomiting • Hair loss • Diarrhea • Infection • Pain or swelling in the extremities • Low blood pressure • Shortness of breath • Decreased number of blood cells that help to clot blood • Stomatitis (mouth sores) • Hemorrhage • Hypertension (high blood pressure) • Hyponatremia (low sodium level)
Rare • Bleeding of the gastrointestinal tract • Inflammation of the heart or membrane around the heart • Chest pain • Abnormal or irregular heartbeat • Heart failure
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• Pneumonia • Dizziness • Lowered white blood cell count (may make you more likely to get infections) • Kidney failure
Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect a fetus. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth control while on this study. Check with your doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study.
For more information about risks and side effects, ask your doctor.
Risks to Reproduction, Unborn Babies, and Nursing Infants: The drugs used in this research study may affect a fetus/embryo. While participating in this research study, you should not become pregnant, father a baby, or nurse a baby. Let your doctor know immediately if you become pregnant or find out that you are going to be the father of a child. We can provide counseling about preventing pregnancy for either male or female study participants.
Laboratory studies have been done to test for any possible reproductive risks. Studies that help us see if ipilimumab may affect your ability to have children have not been done. It is not known whether ipilimumab can cause fetal harm when administered to a pregnant woman or whether ipilimumab can affect reproductive health. It is possible that if the study drugs are given to a pregnant woman it will harm the fetus (unborn baby). Therefore, pregnant women must not take part in this study. Women who could become pregnant will be asked to have a pregnancy test prior to and throughout participation on this study and must use an approved form of birth control during the course of this study and for up to 26 weeks after your last infusion with ipilimumab. Tell your doctor immediately if you suspect you have become pregnant.
You must use birth control while participating in this study. If you are able to have children, you must always use a type of birth control (such as the “pill”) that your study doctor thinks is reliable while you are participating in this study and for 26 weeks after your last infusion with ipilimumab. Your study doctor should be informed of any hormonal contraception (oral contraceptives, implantable or injectable agents) not prescribed by him/her. The purpose of this is to identify any potential interactions between the product on study and the contraceptive, which might reduce the effectiveness of the contraceptive method. You must have a negative pregnancy test before study medication can be given at each visit. Sexually active males in this study must use appropriate precautions. If sexually active, you must agree to use adequate contraception, for the duration of the study and for 26 weeks Rev. 4/11 after your last infusion of ipilimumab. Practicing abstinence is an acceptable method of contraception.
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There is no information available to know if the treatment under investigation will damage sperm, which could potentially lead to fetal damage. Sexually active males in this study must use appropriate precautions. You are asked to inform your study doctor if your partner becomes pregnant while you are enrolled in this clinical trial, and you and your partner will be asked to provide information about the pregnancy outcome. The Sponsor has not set aside any funds to pay for any aspects of obstetric, child, or related care and does not plan to pay for them. If you become pregnant, suspect pregnancy, if you have a change in your menstrual cycle, or change in your contraception method, you should immediately contact your doctor. Should you become pregnant during the study, you will be withdrawn from the study immediately and should seek care from a doctor who specializes in pregnant women (an OB/GYN, or obstetrics and gynecologist physician). If you become pregnant during the study, the sponsor has no plan or policy to reimburse you for medical costs associated with the pregnancy, or for the cost of your child's care.
In the case of a pregnancy your doctor will ask you to agree to allow access to your medical records and to the medical records of your infant for a minimum of 8 weeks after delivery.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
Taking part in this study may or may not make your health better. While doctors hope that the combination of ipilimumab and GM-CSF will be more useful against cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about these two drugs in combination as a treatment for cancer. This information could help future cancer patients.
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY?
Your other choices may include: • Getting treatment or care for your cancer without being in a study • Taking part in another study • Getting no treatment • Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible. Talk to your doctor about your choices before you decide if you will take part in this study.
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WILL MY MEDICAL INFORMATION BE KEPT PRIVATE?
The Eastern Cooperative Oncology Group (ECOG) is conducting this study. ECOG is a cancer research group that conducts studies for the National Cancer Institute. Your doctor is a member of ECOG or another group that is participating in this study. To help protect your privacy, ECOG has obtained a Confidentiality Certificate from the Department of Health and Human Services (DHHS).
With this Certificate, ECOG cannot be forced (for example, by court subpoena) to disclose information that may identify you in any federal, state or local civil, criminal, administrative, legislative or other proceeding. Disclosure will be necessary, however, upon request of DHHS for audit or program evaluation purposes.
You should know that a Confidentiality Certificate does not prevent you or a member of your family from voluntarily releasing information about you or your involvement in this research. If an insurer or employer learns about your participation and obtains your consent to receive research information, then ECOG may not use the Certificate of Confidentiality to withhold this information. This means that you and your family must also actively protect your privacy.
You should also understand that your doctor and ECOG may take steps, including reporting to authorities, to prevent you from seriously harming yourself or others.
Finally, the Certificate does not prevent the review of your research records under some circumstances by certain organizations for an internal program audit or evaluation. Organizations that may inspect and/or copy your research records for quality assurance and data analysis include groups such as:
• Eastern Cooperative Oncology Group (ECOG) • National Cancer Institute (NCI) • Food and Drug Administration (FDA) • Other regulatory agencies and/or their designated representatives • Drug manufacturers and/or their representatives • Central laboratories, banks, and/or reviewers • Bristol-Myers Squibb (BMS) • Genzyme Corporation
[Note to Local Investigators: The NCI has recommended that the local institution address HIPAA regulations. The regulations may or may not be included in the informed consent form depending on local institutional policy.]
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WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment.
The Division of Cancer Treatment and Diagnosis, NCI, will provide the investigational study drug ipilimumab free of charge to all participants. If ipilimumab becomes commercially available for this indication, there is a remote possibility that you may be asked to purchase subsequent supplies. Your physician will discuss this with you should this situation arise.
Genzyme will provide the investigational study drug GM-CSF free of charge to all participants on Arm A for the duration of the study.
The costs of additional laboratory tests, such as pregnancy tests, may not be covered by your insurance.
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site at:
http://cancer.gov/clinicaltrials/understanding/insurance-coverage
You can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?
It is important that you tell your doctor, ______[investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at ______[telephone number].
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.
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WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY?
Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution.
We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?
You can talk to your doctor about any questions or concerns you have about this study. Contact your doctor ______[name(s)] at ______[telephone number].
For questions about your rights while taking part in this study, call the ______[name of center] Institutional Review Board (a group of people who review the research to protect your rights) at ______(telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] *You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) at 888-657-3711 (from the continental US only). [*Only applies to sites using the CIRB.]
Please note: This section of the informed consent form is about additional research studies that are being done with people who are taking part in the main study. You may take part in these additional studies if you want to. You can still be a part of the main study even if you say “no” to taking part in any of these additional studies.
You can say “yes” or “no” to each of the following studies. Please mark your choice for each study.
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Rev. 12/10 ABOUT PROVIDING SPECIMENS FOR RESEARCH
Please read this form and ask about anything that is not clear to you. This is part of the informed consent process for research. This is to inform you of the possible risks, benefits, and limits of giving your samples for research. ______
You are being asked to give some of your samples (called specimens) and related information to be stored (banked) for future research. This may help researchers learn more about how to prevent, find and treat cancer and other diseases.
The choice to have your samples used for research is up to you. No matter what you decide, it will not affect your medical care.
Below is some general information you should know before agreeing to allow the use of your specimens for research. After the general information there are descriptions of the research projects. Each project is described separately, including the types of samples requested and how they are collected. Each description is followed by questions concerning your participation in the project. Your samples will be used only for the projects in which you agree to participate. ______
What are samples and where are they stored?
A sample is any material taken from your body such as tissue, blood, urine and other fluids.
If you agree, your samples will be sent to laboratories to be used in research or will be stored for research in a Cooperative Group bank. These banks are supported by the National Cancer Institute. Cooperative Group banks contain samples and information. Your samples are kept along with those from other people in the banks. Researchers then ask for samples from the banks to study them.
What information will be collected?
When your samples are sent to any research laboratory or bank from your treating institution, some personal information will be sent with the samples. Any personal information sent with the samples is not given to other researchers. The personal information is used only by the laboratory or bank to identify your samples. Your privacy will be protected to the fullest extent possible. This will be discussed later in the section “How will information related to my samples be protected?”
Examples of other information that might be used for research include:
Dates of medical procedures Any diagnosis and stage of your disease (if you have cancer) Your age and race Medical and family history Treatments you had How you responded to treatments
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What will happen to my samples if I agree to give them for research? If you agree to let your samples be kept for future research (research not yet defined), your samples will be stored in a Cooperative Group bank. The samples will be kept until they are used up or destroyed. The samples are given a code to protect your privacy before they are used. Any related information given to researchers will also be coded. Researchers will receive the code instead of any information that might directly identify you. You or your doctor will not be given reports or other information about the research that uses your samples. This information will not be put into your health record. Results may be used for future research. You will not be named or identified by other personal information if any results are published. Most publications contain results from many patients. Your samples and related information will be used only for research and will not be sold. It is possible that research may help to create new products or treatments. If this should happen, you will not be paid. Coded data from some research studies that use samples could be put into secure Internet databases that can be shared by other approved researchers. This could include genetic data. Current safety rules are followed to safeguard your privacy. Your name or contact information will not be put in the database.
What kind of research will be done with my samples?
Many types of research use normal or diseased (cancerous) samples. Researchers can study proteins, RNA and DNA (genes). The study of genes (DNA) is often called genetic research.
For example, your samples may be looked at: • To see if a trait is passed down in families from one generation to the next (inherited). This type of research may help to explain why some cancers run in families or why some people have side effects from treatment while others do not. This is often studied through blood cells and DNA (genes). • To learn about changes in the body that happen after you were born (non-inherited). For example, being in the sun too much can cause changes in cells that lead to skin cancer.
Will it help me if I give my samples for research?
Using your samples for research will probably not help you. We do hope the research results will help people in the future. The best way to prevent, find or treat cancer and other diseases is by studying human samples and data.
What are the risks of giving my samples for research?
There is a risk that your information could be misused. The chance of this happening is very small. We have many protections in place to lower this risk. See the next section, “How will the information related to your samples be protected?” Your privacy will be protected to the fullest extent possible.
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There can be a risk in knowing genetic information. New health information about inherited traits that might affect you or your blood relatives could be found during a research study. Even though your genes are unique, you share some of the same genes with your blood relatives. Very rarely health or genetic information could be misused by employers, insurance companies, and others. For example, life insurance companies may charge a higher rate based on this information. Some states have laws to protect against genetic discrimination [list appropriate state information if your state has such laws]. A new federal law called the Genetic Information Non- Discrimination Act, or GINA is in effect. This law helps to lower the risk of health insurance or employment discrimination. The law does not include other types of misuse by life insurance or long term care insurance. To learn more about the GINA Law, please check the Internet or ask the study staff. Although we are not able to know all of the risks from taking part in research, we believe that the risks to you and your family are very low because research results will not be returned to you or your doctor.
How will information related to my samples be protected? We have many ways to protect the information related to your samples: Your samples and information receive a unique code. Researchers only receive coded samples and information, and will not be able to link the code to you. Only approved people in the Eastern Cooperative Oncology Group can match you to the code on your samples and related information. Strict security safeguards are in place to reduce the chance of misuse or unplanned release of information. Steps we take include password protected access to databases and restricted access to freezers or rooms that contain samples. Before samples are given to researchers, studies are reviewed for the quality of the science and for patient protection. Records from research studies can be reviewed by the Cooperative Group, by the sponsor, and by government agencies. This is to make sure the research follows the rules of the Cooperative Group and state or federal laws. Research results will not be returned to you or your doctor. If research results are published, your name and other personal information will not be given. ECOG also has a Certificate of Confidentiality from the U.S. Department of Health and Human Services. The Certificate protects against the forced release of personal information from the Cooperative Group bank or database. What this means is that ECOG cannot be forced to disclose your identity to any third party. It is possible that for some legal proceedings, the Certificate of Confidentiality could be over-ridden by a court of law.
Making your choice
The choice to take part is up to you. You may choose not to let us store and use your samples. If you decide not to let us store and use your samples, you will still receive the same medical care and you may still participate in the treatment part of this clinical trial. You may also take part in other research studies.
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If you decide that your samples can be kept, you may change your mind at any time. Contact the study staff at your hospital and let them know that you do not want your samples used for research [Insert contact number]. Then, any sample that remains in the bank will no longer be used. Samples that have already been given to or used by researchers cannot be returned or destroyed.
Please read the research study descriptions below, review the questions carefully and circle “Yes” or “No”. If you have any questions, please talk to your doctor or nurse, or call the institution’s research review board at [IRB's phone number].
USING SPECIMENS FOR FUTURE RESEARCH
We would like to keep the specimens that are leftover from the central review for future research.
Additionally, we would like to collect blood for banking for future research. The specimens will be collected by using a needle to draw some blood from a vein in your arm. If you agree, approximately seven to eight tablespoons of blood will be collected before you start treatment, seven to eight tablespoons will be collected every six weeks during the induction phase of treatment, seven to eight tablespoons will be collected every twelve weeks during the maintenance phase of treatment, and seven to eight tablespoons will be collected at the end of study assessment. We would also like, for future research, to have additional samples of your tumor tissue which were collected to treat, diagnose or monitor your disease, including samples that may be obtained after you have completed or discontinued your treatment.
Although most future research studies will focus on cancer, some research projects may also include other diseases, such as heart disease, diabetes or Alzheimer’s disease.
As indicated above, the specimens will only be given to researchers approved by scientific reviewers appointed by the Eastern Cooperative Oncology Group. Any research done on the specimens must also be reviewed by the researcher's institutional review board.
May we have some blood for future research about cancer? I agree to provide additional blood for research. Yes No May we have additional tissue from your surgeries or biopsies, if available, for future research about cancer? I agree my tissue will be submitted for research. Yes No We would like to keep any tissue leftover after the central review for future research about cancer. My specimens may be kept for use in research to learn about, prevent, treat, or cure cancer. Yes No
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May we keep any samples submitted for future research about other diseases. My specimens may be kept for research about other health problems (for example: causes of diabetes, Alzheimer's disease, or heart disease). Yes No
PERMISSION TO CONTACT YOU IN THE FUTURE We request your permission to contact you in the future about taking part in more research studies. If you agree and we decide to contact you in the future, we will first contact your doctor or some one at your hospital. They will tell you why we would like to contact you and, if you agree, they will send us your contact information. We will not attempt any direct contact without obtaining this second permission from you.
Someone from this institution may contact me in the future to ask me to take part in more research.
Yes No
WHERE CAN I GET MORE INFORMATION?
You may call the National Cancer Institute's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615
You may also visit the NCI Web site at http://cancer.gov/
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form. If you want more information about this study, ask your doctor.
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SIGNATURE
I have been given a copy of all _____ [insert total of number of pages] pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study.
Participant ______
Date ______
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Appendix II Pathology Submission Guidelines
The following items are included in Appendix II: 1. Guidelines for Submission of Pathology Materials (instructional sheet for Clinical Research Associates [CRAs]) 2. Instructional memo to submitting pathologists 3. List of Required Materials for E1608 4. ECOG Pathology Submission Form (#638 v04.2)
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Guidelines for Submission of Pathology Materials
The following items should always be included when submitting pathology materials to the ECOG Pathology Coordinating Office: • Institutional Surgical Pathology Report • Pathology materials (see attached List of Required Material) • ECOG Pathology Material Submission Form (#638 v04.2)
Instructions: 1. Place the Patient ID label provided by the ECOG Coordinating Center in Part A of the ECOG Pathology Material Submission Form. If a label is not available, TYPE or PRINT the following information in Part A of the form: Patient's name (last, first) Protocol number Protocol case number (the patient's ECOG sequence number; for intergroup studies, include both the ECOG and other group's sequence numbers) Patient's hospital number Institution Affiliate (if appropriate) 2. Complete blank areas of the pathologist's instructional memo and forward it, along with the List of Required Material and the ECOG Pathology Material Submission Form, to the appropriate pathologist. 3. The pathologist should return the required pathology samples and surgical pathology reports, along with the completed ECOG Pathology Material Submission Form (#638 v04.2) (Part B completed). If any other reports are required, they should be obtained from the appropriate department at this time. 4. Keep a copy of the ECOG Pathology Material Submission Form (#638 v04.2) for your records. (The original should be sent to the PCO.) 5. Double-check that ALL required forms, reports and pathology samples are included in the package to the Pathology Coordinating Office. (See appropriate List of Required Material.) Pathology specimens submitted WILL NOT be processed by the Pathology Coordinating Office until all necessary items are received. 6. Mail pathology materials to: ECOG Pathology Coordinating Office Robert H. Lurie Comprehensive Cancer Center of Northwestern University Medical School Olson Pavilion - Room 8421 710 North Fairbanks Court Chicago, IL 60611 If you have any questions concerning the above instructions or if you anticipate any problems in meeting the pathology material submission deadline of one month, contact the Pathology Coordinator at the ECOG Pathology Coordinating Office by telephone (312) 503-3384 or by fax (312) 503-3385.
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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Coordinating Center Frontier Science 900 Commonwealth Avenue • Boston, MA 02215 Eastern Cooperative (617) 632-3610 • Fax: (617) 632-2990 Oncology Group Randomization: (617) 632-2022
Group Chair: Robert L. Comis, M.D. Jean MacDonald, Director of Research Operations Group Statistician: Robert Gray, Ph.D. Mary Steele, Director of Group Administration
Revised 4/12, Addendum #5
MEMORANDUM TO: ______(Submitting Pathologist) FROM: Stanley Hamilton, M.D., Chair ECOG Laboratory Science and Pathology Committee DATE: ______SUBJECT: Submission of Pathology Materials for E1608: A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Rev. 4/12 The patient named on the attached ECOG Pathology Material Submission Form (#638 v04.2) has been entered onto an ECOG protocol by ______(ECOG Investigator). This protocol requires the submission of pathology materials for pathology review and banking. Please complete PART B of the Submission Form. Keep a copy for your records and return the completed Submission Form, the surgical pathology report(s), the slides and/or blocks and any other required material (see List of Required Material) to the Clinical Research Associate (CRA). The CRA will forward all required pathology material to the ECOG Pathology Coordinating Office. Blocks and/or slides submitted for this study will be retained at the ECOG Central Repository for future studies. Blocks will be returned for purposes of patient management care upon request. Rev. 4/12 If you have any questions regarding this request, please contact the Pathology Coordinating Office at (312) 503-3384 or FAX (312) 503-3385. The ECOG CRA at your institution is: Name: ______Address:______Phone: ______
Thank you.
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LIST OF REQUIRED MATERIAL
E1608: A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Baseline (submit within one month of patient registration) 1. ECOG Pathology Material Submission Form (#638 v04.2) – Parts A & B completed. 2. Institutional pathology report (must be included with EVERY pathology submission). 3. Pathology Materials: • Paraffin block from primary tumor of melanoma and subsequent tumor metastases Post Therapy (submit within one month of collection) 1. ECOG Pathology Material Submission Form (#638 v04.2) – Parts A & B completed. 2. Institutional pathology report (must be included with EVERY pathology submission). 3. Pathology Materials: • Paraffin block from post therapy tumor Rev. 12/10 NOTE: If blocks cannot be submitted, please send one (1) H&E and twenty (20) unstained sections from the thickest portion of the tumor.
Rev. 4/12 NOTE: Submission of pathology materials for diagnostic review is mandatory in order for the patient to be considered evaluable. NOTE: A copy of the completed submission form will be sent to the Coordinating Center by the Pathology Coordinating Office.
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PART A: To Be Completed By Data Manager/CRA DO NOT USE INITIALS – Submit Patient’s FULL Name (The Patient has authorized the use of PHI.)
Date sample sent to ECOG ______/______/______(M,D,Y) Patient’s Name: Data Manager ______Last ______First ______Address ______ECOG Prot. No. ______ECOG Patient Seq. No. ______Participating Group Participating Group Prot. No.______Patient ID No. ______Telephone No. ( ) ______Group______Institution______PI ______Fax No. ( )______Step No.______Affiliate______Email address ______ECOG Parent Prot. No. ______Seq. No. ______
PART B: TO BE COMPLETED BY DATA MANAGER/CRA AND SUBMITTING PATHOLOGIST PCO-RL Use Only Date Specimen Number of Specimen ID PCO ID Status* Disease Site Type of Stain (See Below) Collected (M/D/Y) Slides/Vials Numbers Numbers Complete for / / Slides/Vials
/ /
Date Specimen Number of Specimen ID PCO ID Status* Disease Site Fixative (See Below) Collected (M/D/Y) Blocks/Punch Numbers Numbers Complete for / / Blocks/Punch
/ /
*Status: Please identify the clinical status of the sample. List all that apply: 1. Original diagnostic material 5. Post-surgery biopsy/tissue Submitting Pathologist______2. AML/MDS diagnosis 6. Relapse/recurrence Telephone No. ( ) ______3. Pre-protocol treatment 7. Remission/response biopsy/tissue Address ______4. Post-protocol treatment 8. Other, specify:______biopsy/tissue ______
Did the patient consent to participate in the storage of samples for future research? Yes No
MATERIAL RETURN (All materials will be retained by the ECOG PCO unless return is requested here.) Does the submitting institution’s policy require the return of any submitted material (blocks, H&E slides, etc.)? ...... Yes No If so, please indicate which materials must be returned ______All materials will be returned to the submitting pathologist unless an alternate address is indicated here ______
If materials were not able to be submitted for this protocol and its correlative studies, please circle the reason for non-submission. Attach a formal letter referencing regulations, policy, and/or other explanation. If possible, include a copy of the policy. Federal/State Regulations ______Hospital/Institutional Policy _____ Insufficient Tissue ______Other ______(Specify) ______(PCO-RL Use Only) Pathologist of Investigator’s Signature______PV ______
PART C: ECOG PATHOLOGY COORDINATING OFFICE USE ONLY Date Sample Received at PCO _____/_____/_____ Date Sent to Reviewer _____/_____/_____ Date Sent to PI/Central Lab _____/_____/_____ Site Compliance %______Name of Reviewer ______PI/Central Lab ______PCO Comments: ______Staff Init. ______Investigator: Keep a copy for your files and submit original form to the destination specified in protocol. 2/05
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Appendix III
Patient Thank You Letter
We ask that the physician use the template contained in this appendix to prepare a letter thanking the patient for enrolling in this trial. The template is intended as a guide and can be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, physicians may elect to further tailor the text to their situation. This small gesture is a part of a broader program being undertaken by ECOG and the NCI to increase awareness of the importance of clinical trials and improve accrual and follow-through. We appreciate your help in this effort. ______
[PATIENT NAME] [DATE] [PATIENT ADDRESS]
Dear [PATIENT SALUTATION],
Thank you for agreeing to take part in this important research study. Many questions remain unanswered in cancer. With the help of people like you who participate in clinical trials, we will achieve our goal of effectively treating and ultimately curing cancer. We believe you will receive high quality, complete care. I and my research staff will maintain very close contact with you. This will allow me to provide you with the best care while learning as much as possible to help you and other patients. On behalf of [INSTITUTION] and the Eastern Cooperative Oncology Group, we thank you again and look forward to helping you.
Sincerely,
[PHYSICIAN NAME]
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Appendix IV
Suggested Work-up and Treatment for IMMUNE-Related Adverse EVENTS (IRAEs)
An IRAE is defined as an adverse event of unknown etiology, associated with drug exposure and is consistent with an immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an adverse event a non-dermatologic, immune-mediated event. Serological, immunological, and histological (biopsy) data should be used to support the diagnosis of an immune-mediated toxicity. Documentation of test results should be included in the patient’s medical record. Gastrointestinal (diarrhea) and skin (rash)-related toxicities have been the most common IRAEs noted in prior studies with ipilimumab. Suggested work-up procedures for suspected IRAEs of the gastrointestinal tract, liver, skin, eye, pituitary, and adrenal gland are listed below. When symptomatic therapy is inadequate or inappropriate, an IRAE should be treated with steroids followed by a slow taper. Gastrointestinal Tract: Diarrhea (defined as either first watery stool, or increase in frequency 50% above baseline with urgency or nocturnal bowel movement, or bloody stool) should be further evaluated and infectious or alternate etiologies ruled out. Patients should be advised to inform the investigator if any diarrhea occurs, even if it is mild. An algorithm for working up patients with diarrhea or suspected colitis is provided in Appendix 4. If the event is of significant duration or magnitude or is associated with signs of systemic inflammation or acute phase reactants (e.g., increased CRP or platelet count; or bandemia), it is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 3 to 5 specimens for standard paraffin block be performed. If possible, 1 to 2 biopsy specimens should be snap frozen and stored. All patients with confirmed colitis should also have an opthomological examination, including a slit-lamp exam, to rule out uveitis. Tests should also be performed for WBCs and for stool calprotectin. Patients with colitis should discontinue any non-steroidal anti-inflammatory medications or any other medications known to exacerbate colitis symptoms. Investigators should use their clinical judgment as to whether corticosteroids are necessary to treat colitis associated with ipilimumab therapy and as to what dose should be used. As guidance prior experience suggests that colitis manifested as ≥ Grade 3 diarrhea requires corticosteroid treatment. For severe symptoms, prednisone 60 mg or equivalent may be required to control initial symptoms and the dose should be gradually tapered over at least one month in duration. Lower doses of prednisone may be considered for less severe cases of colitis. It is suggested that prednisone (for oral administration) or solumedrol (for intravenous administration) be corticosteroid of choice in the treatment of colitis. Liver: Elevation of LFTs ≥ 3 fold from baseline should instigate an investigation into the underlying etiology for suspected IRAEs. Neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and bile duct should be performed to rule out neoplastic or other causes for the increased LFTs. An ANA, pANCA, and anti-smooth muscle antibody test should be performed if an autoimmune etiology is considered. Consultation with a hepatologist is appropriate for a suspected liver IRAE and a biopsy should be considered. Patients presenting with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should have LFTs performed immediately and reviewed before administering the next dose of study drug. Treating physicians should discuss, with the CRO Medical Monitor, unexplained increases in LFTs ≥ 3 fold from baseline prior to any additional study drug administration. Pancreas: Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of pancreatitis, may rarely be associated with anti-CTLA-4 monoclonal antibody administration. The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate workup should include serum amylase and lipase tests.
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Skin: A dermatologist should evaluate persistent and/or severe rash or pruritis. A biopsy should be performed if appropriate and if possible, photos of the rash should also be obtained. Low-grade ipilimumab mediated rash and pruritis IRAEs have been treated with symptomatic therapy (e.g., antihistamines). Topical or parenteral corticosteroids may be required for more severe symptoms. Eye: An ophthalmologist should evaluate visual complaints with examination of the conjunctiva, anterior and posterior chambers and retina; visual field testing and an electroretinogram should also be performed. Patients with ipilimumab related uveitis or episcleritis have been treated with topical corticosteroid eye drops. Endocrine: Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status changes, or constipation should be investigated for the presence of thyroid, pituitary or adrenal endocrinopathies. An endocrinologist should be consulted if an endocrinopathy is suspected. TSH and free T4 levels should be obtained to determine if thyroid abnormalities are present. TSH, prolactin and a morning cortisol level will help to differentiate primary adrenal insufficiency from primary pituitary insufficiency. Appropriate hormone replacement therapy should be instituted if an endocrinopathy is documented. Suspected irAEs should be documented in the patient’s medical record.
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Appendix V
Recommended Diarrhea Management Algorithm
GRADE 1 GRADE 2 GRADE 3 GRADE 4 GRADE 5 Increase of < 4 Increase of 4-6 stools Increase of ≥ 7 Life-threatening Death stools per day per day over baseline; stools per day over consequences over baseline; IV fluids indicated < 24 baseline; incon- (eg, hemodynamic mild increase in hrs; moderate increase tinence; IV fluids collapse) ostomy output in ostomy output ≥ 24 hrs; compared with compared to baseline; hospitalization; baseline not interfering with ADL severe increase in ostomy output compared to baseline; interfering with ADL
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Appendix VI
Recommended Hepatotoxicity Management Algorithm
The most current experience with immune-related hepatitis has allowed further development of this management algorithm to include recommendations for treatment.
HEPATOTOXICITY THERAPEUTIC INTERVENTION ALGORITHM
Situation: rising liver function tests (LFTs) > 8X ULN or suspected immune-mediated hepatitis
1) Admit subject to hospital for evaluation and close monitoring 2) Stop further ipilimumab dosing until hepatotoxicity is resolved. Consider permanent discontinuation of ipilimumab per protocol (Section 5.5.1 of protocol) 3) Start at least 120 mg methylprednisolone sodium succinate per day, given IV as a single or divided dose 4) Check liver laboratory test values (LFTs, T-bilirubin) daily until stable or showing signs of improvement for at least 3 consecutive days 5) If no decrease in LFTs after 3 days or rebound hepatitis occurs despite treatment with corticosteroids, then add mycophenolate mofetil 1g BID per institutional guidelines for immunosuppression of liver transplants (supportive treatment as required, including prophylaxis for opportunistic infections per institutional guidelines) 6) If no improvement after 5 to 7 days, consider adding 0.10 to 0.15 mg/kg/day of tacrolimus (trough level 5- 20 ng/mL) 7) If target trough level is achieved with tacrolimus but no improvement is observed after 5 to 7 days, consider infliximab, 5 mg/kg, once 8) Continue to check LFTs daily for at least 2 weeks to monitor sustained response to treatment
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A flow chart of the algorithm is depicted in the following page.
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Appendix VII
Recommended Endocrinopathy Management Algorithm
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Immunologic Monitoring UPCI Research Pavilion at the Hillman Cancer Center Laboratory Room 1.26 5117 Centre Avenue Pittsburgh, PA 15213-1863 Telephone: 412.624.0078 Fax: 412.623.6625
Appendix VIII Shipping Kit Request Facsimile Form
ECOG—PROTOCOL 1608
To: ECOG Study Coordinator Fax: 412-623-6625
From: Name: ______
Institution: ______
Telephone: ______
Fax: ______
Number of Kits Requested: ______
Shipping Address: ______
______
______
______
______
PLEASE ALLOW 10 WORKING DAYS FOR RECEIPT OF SHIPPING KITS.
This message is intended only for the use of the individual or entity to which it is addressed and may contain information that is privileged, confidential, and exempt from disclosure under applicable law. If the reader of this message is not the intended recipient or the employee or agent responsible for delivering the message to the intended recipient, you are hereby notified that any dissemination, distribution, or copying of this communication is strictly prohibited. If you have received this communication in error, please notify us immediately by telephone and return the original facsimile to us at the above address via the U.S. Postal Service. Thank you.
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Immunologic Monitoring UPCI Research Pavilion at the Hillman Cancer Center Laboratory Room 1.26 5117 Centre Avenue Pittsburgh, PA 15213-1863 Telephone: 412.624.0078 Fax: 412.623.6625
Appendix IX Specimen Shipment/Requisition Form
ECOG PROTOCOL E1608
Ship specimens by overnight express to arrive the next morning unless otherwise directed by the protocol. Do NOT ship on Friday or Saturday, or the day before a legal holiday.
Rev. 4/12 Call the IMCPL ECOG Study Coordinator at 412-624-0078 with questions on shipping.
Please complete the following information and include this form in the shipment:
ECOG Patient Sequence Number: ______ECOG Patient Initials ______-- _____ Last First
Clinical Site: ______Site Contact: ______
Telephone Number: ______Fax Number: ______
Federal Express® Air Bill No.:______Date of Shipment: ______
Specimen Specimen Collection Date __ __/__ __/__ __ Collection Time __ __: __ __ mm dd yy (24 hour clock)
Specimens: At EACH Time Point submit One (1) Red Top Tube and Ten (10) Green Top Tubes for both Serum and Peripheral Blood Mononuclear Cells
Time Points (check one):
□ Baseline One (1) red top tube and Ten (10) green top tubes □ Every Six Weeks (Induction) One (1) red top tube and Ten (10) green top tubes □ Every 12 weeks (Maintenance) One (1) red top tube and Ten (10) green top tubes □ End of Study Assessment One (1) red top tube and Ten (10) green top tubes
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NOTE: Serum and PBMC are to be collected at each time point.
Shipping checklist: (kits will be shipped / delivered to you from UPCI IMCPL upon request) _____ Label vials with patient initials/sequence number, and date and time of draw. Rev. 4/12 _____ STS Shipping Manifest Form _____ Seal, wrap, and place specimen tubes in specimen shipper kit. _____ If STS is unavailable, complete the Specimen Requisition/Shipment Form and ECOG Form #2981, make a copy for your records, and place the original Forms inside the specimen shipper kit. Please check day of week on which sample is being shipped:
□ Monday through Thursday Rev. 4/12 □ Day Prior to a Legal Holiday (Requires 7 days’ prior notice and authorization from the IML)
To be completed by IML Staff: IML Study Number:
IML Accession Number: Specimen Type received (if different from above):
Specimen Acceptability: Comment:
This message is intended only for the use of the individual or entity to which it is addressed and may contain information that is privileged, confidential, and exempt from disclosure under applicable law. If the reader of this message is not the intended recipient or the employee or agent responsible for delivering the message to the intended recipient, you are hereby notified that any dissemination, distribution, or copying of this communication is strictly prohibited. If you have received this communication in error, please notify us immediately by telephone and return the original facsimile to us at the above address via the U.S. Postal Service. Thank you.
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Appendix X Medication Diary
Please complete this diary on a daily basis. Write in the amount of the dose of GM-CSF that you took in the appropriate “Day” box.
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. If you experience any health/medical complaints or take any medication other than those in this study, please record this information. Other study drugs will be administered by a healthcare professional. As a result, patients do not have to record these treatments in this diary.
Cycle # (Month):
Week of: ______
Study Drug Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
GM-CSF
Week of: ______
Study Drug Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14
GM-CSF
Week of: ______
Study Drug Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21
No Drug No Drug No Drug No Drug No Drug No Drug No Drug GM-CSF (day off) (day off) (day off) (day off) (day off) (day off) (day off)
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HEALTH/MEDICAL COMPLAINTS Please record all health/medical complaints you may have experienced below.
Please describe what you experienced Date started Date stopped
OTHER MEDICATION Record only medication (prescription and/or over-the-counter, including herbal medications and vitamins) taken other than lenalidomide or prednisone.
Why did you take the Name of Medication Date medication started? Date medication stopped medication?
______Patient Signature ______Date
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Appendix XI E1608 Cooperative Research and Development Agreement (CRADA)
The ipilimumab supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between Bristol-Myers Squibb (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing investigational Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other investigational Agent(s), each the subject of different collaborative agreements , the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data.”):
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own investigational Agent.
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own investigational Agent. 3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order. Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them. 5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.
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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI Executive Plaza North, Suite 7111 Bethesda, Maryland 20892 FAX 301-402-1584 Email: [email protected]
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ proprietary information.
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma Appendix XII E1608 GM-CSF Drug Request Form
Rev. 4/12 Date Date of Protocol No./Title: Needed Request: E1608 By: A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma Attention:
Ship Address:
PI: Site#
Phone#: Fax#: Institution: Email:
Patient Sequence Units Qty Study Drug Requested Number
GM-CSF
Please email the completed form to: [email protected] or fax to: 210-949-8484. Allow 3 business days from date of request to date of delivery. There are no weekend deliveries. For questions regarding shipments, please contact Karen Craun @ 210-949-8607 or Jill Twardowski @ 210-949-8225.
Do not write below this line. For Genzyme Use Only Medical Affairs The following documents are required for initial shipments: 1. IRB Approval Letter……………………………. Y N N/A 2. Signed Research Agreement………………… Y N N/A 3. IND Status document………………………….. Y N N/A 4. clinicaltrials.gov listing…………………………. Y N N/A 5. IACUC Approval Letter (Pre-clinical only)…… Y N N/A
Signature: ______Date: ______Fax this form to CPRS: 508-424-4484
CPRS Processed by: ______Date: ______Reviewed by: ______Date: ______
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Appendix XIII Certificate of Destruction of Clinical Trial Drugs
Instructions: Complete this form when all patients have completed treatment at your institution. All unused drugs, partially used, expired, or empty containers must be destroyed according to institutional policy for drug destruction. `A copy of this form should be faxed to Genzyme Clinical Pharmacy Research Services (CPRS) at 508-424-4484.
A copy should be maintained with the drug accountability records for this protocol.
Sponsor: Genzyme/ECOG ECOG Study No. E1608 Genzyme Study No. iLEUK034 DPM: Genzyme CPRS
Investigator Name: Investigator CTEP ID Number: Investigator Address:
Drug Name Lot Number Expiry Date Amount Amount Number of vials Used Unused destroyed at site GM CSF
Reason for destruction: ______Method & Location of destruction: ______Date of Destruction: ______
I confirm the above material has been destroyed in a safe and appropriate manner. Name and Title: ______Date: ______Signature: ______PI Signature: ______
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Appendix XIV Self-Administration Guide for GM-CSF
Rev. 4/11 IMPORTANT NOTE: Please read ALL information about GM-CSF in this Appendix before administering any injections.
Rev. 4/11 IMPORTANT: STORAGE OF GM-CSF • GM-CSF should be stored in the refrigerator but not in the freezer compartment. • Do not shake GM-CSF. • Do not freeze or use GM-CSF that has been frozen. • Keep GM-CSF out of direct sunlight. • Do not use GM-CSF beyond the expiration date printed on the vial label. • GM-CSF older than 20 days should be returned to the hospital for proper destruction. • All unused, partially used, expired or empty containers of GM-CSF should be returned to the hospital for proper destruction.
INSTRUCTIONS FOR PREPARING AND GIVING A SELF-INJECTION Important to use correct syringe and dose • If your doctor has recommended that you take GM-CSF at home, your doctor, nurse, or pharmacist should have instructed you and/or your caregiver on how GM-CSF should be prepared, how it should be injected, and how often it should be injected. • It is very important that you use the correct needle and syringe. Failure to use the correct syringe could result in your receiving either too little or too much GM-CSF. If you receive too little GM-CSF, it may not be effective. If you receive too much GM-CSF, your white blood cell count may get too high, which may be harmful. • The dose will usually be measured in milliliters (mL) or cubic centimeters (cc). (For example: 0.8 mL or 0.8 cc). It is important that you use a syringe that is marked in tenths (1/10) of a milliliter or cubic centimeter (for example: 0.1, 0.2, 0.3, 0.4, 0.5, etc. ... to 1.0 mL or cc) so that you are able to measure the correct dose prescribed by your doctor. A 3 cc syringe with a 25 to 30 gauge 5/8-inch needle or the syringe and needle size specified by your doctor may be used. Your doctor will either supply you with the correct syringes and needles, or will write you a prescription so you can get the correct syringes and needles from your pharmacy. • Your dose has been selected to meet your individual needs. Do not change your dose without consulting your doctor. • If you are not sure about the amount (mL or cc) or dose to be used, talk to your doctor, nurse, or pharmacist.
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GIVING YOURSELF AN INJECTION Before using GM-CSF for the first time, talk to your doctor, nurse, or pharmacist about how to use it, what to expect when using it, possible side effects, and what to do if side effects occur. You must be instructed and trained properly in how to prepare and inject GM-CSF by your doctor, nurse, or pharmacist prior to using it. Administer GM-CSF the same time every day, preferably at night. Do not attempt to self-administer GM-CSF until you are sure that you understand the instructions for giving an injection to yourself. Your dose has been selected to meet your individual needs. Do not change your dose without consulting your doctor. If you are unsure about the amount (mL or cc) or dose to be used, how to inject yourself, or how often to inject yourself, talk to your doctor, nurse, or pharmacist. IMPORTANT: IT IS VERY IMPORTANT THAT YOU CAREFULLY READ THESE INSTRUCTIONS AND FOLLOW THEM EXACTLY IN ORDER TO HELP AVOID CONTAMINATION OF THE GM- CSF AND POSSIBLE INFECTION.
INJECTION SITE Choosing an Injection Site Your doctor, nurse, or pharmacist has instructed you on how to give yourself a subcutaneous (under the skin) injection of GM-CSF. The best areas for self-injecting GM-CSF are the thighs or stomach. The navel and waistline should be avoided. If a caregiver is helping with the injections, you may be instructed to inject on the back portion of the upper arms. It is a good idea to know where your injection will be given before you prepare your dose.
Rotating Injection Sites It is important to use a different injection site each time to avoid soreness in any one area. A new injection should not be given in the same area as the last injection. It is a good idea to alternate your injection sites from one thigh to the stomach and then to the other thigh. This is called rotating your injection sites. Injection sites should be at least one inch apart. Do not choose an area where the skin is tender, bruised, red, or hard. To keep track of your injection sites, keep a record of where and when you give yourself an injection. One way to do that is to note the injection site on a calendar or in a diary along with the date you first used the vial. If all areas become tender, talk to your doctor, nurse, or pharmacist about choosing other injection sites.
Injection Site Skin Reactions Occasionally a skin reaction may occur at the injection site. This usually will not require you to stop taking GM-CSF. The skin may become red, painful, or swollen. If a skin reaction occurs, contact your doctor. The following steps may be taken to help prevent further skin reactions: • At least 30 minutes before you plan to inject, remove your GM-CSF from the refrigerator and allow it to come to room temperature before injecting. • Rotate the injection sites from one injection to the next. • Apply ice to the site for one minute immediately prior to injection. • Inject GM-CSF slowly. • Avoid rubbing the skin before or after injecting.
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Remove GM-CSF From the Refrigerator and Inspect the Vial and Contents • Take the GM-CSF vial out of the refrigerator at least 30 minutes before you plan to inject, allowing it to come to room temperature. Do not leave the vial in direct sunlight. • Check the date on the label to make sure the GM-CSF has not expired; if it has, contact your doctor, nurse,or pharmacist for further instructions. GM-CSF should be clear and colorless. If it is not, or if the GM-CSF appears to contain lumps, flakes, or particles, contact your doctor, nurse, or pharmacist. • DO NOT SHAKE the vial. Shaking the vial could cause froth or bubbles to appear. Although this will not affect how well GM-CSF will work, it could decrease the amount of GM-CSF that you are able to draw into the syringe. If the GM-CSF looks frothy or bubbly, use another vial. Return the frothy or bubbly vial to the refrigerator and allow it to settle for use on another day.
Gather Your Supplies and Prepare Your Work Area • Select a clean, convenient, well-lit location to lay out your supplies. It is a good idea to wipe down the area with an alcohol swab to make sure it is germ-free. Gather the following supplies along with the GM-CSF: A sterile syringe and needle (as specified by your doctor, nurse, or pharmacist) Prepackaged alcohol swabs Ice pack
Rev. 4/11 A puncture-resistant container for disposal of the needle and syringe (see the section on page 5 titled “Dispose of Supplies” regarding proper disposal container)
Choose and Prepare the Injection Site • Wash your hands thoroughly with soap and warm water, and dry them with a clean towel. This should be done just before cleaning the injection site and preparing the GM-CSF dose. • Choose an injection site. Do not choose an area where the skin is tender, bruised, red, or hard. As you have been instructed, choose a different site with each injection. Today’s injection should not be given in the same area as your last injection. To keep track of your injection sites, you may want to record the injection site you picked on a calendar or in a diary. For additional information, please refer to the INJECTION SITE section above. • Ice the site for about 1 minute before your injection. Then, with an alcohol swab, wipe the skin where the injection will be made using a gentle circular motion. Allow the skin to dry for about 10 seconds. Set the used alcohol swab aside. Do not re-use this alcohol swab.
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Withdraw the GM-CSF From the Vial • The GM-CSF should now be at room temperature. DO NOT SHAKE the vial. • Flip off the plastic cap from the GM-CSF vial. Do not remove the gray rubber stopper. • Wipe the top of the rubber stopper with a new alcohol swab. Set the used alcohol swab aside. Do not touch the rubber stopper with your hands or fingers. If you do touch the stopper, clean it again with a new alcohol swab. • Remove the syringe and needle specified by your doctor from its packaging. With the cover still on the needle, draw air into the syringe by pulling back on the plunger. The amount of air you draw into the syringe should be equal to your GM-CSF dose. Rev. 4/11 • Carefully remove the needle cover. Do not lay down the syringe or allow the needle to touch anything. If the needle touches any surface, including your hands, throw away the needle and syringe in your disposal container and start over with a new syringe and needle. • With the vial upright, insert the needle downward, through the center of the gray rubber stopper. After the needle penetrates the gray rubber stopper, push the plunger all the way in to inject the air into the vial. Make sure the needle is above the GM-CSF. Try not to inject the air into the GM-CSF because bubbles may form, making it hard for you to withdraw the correct GM-CSF dose. The air you just injected into the vial will make it easier for you to withdraw the GM-CSF into the syringe. Leave the needle in the rubber stopper. • Without withdrawing the needle from the rubber stopper, turn the vial upside down. Then, move the needle tip into the GM-CSF. Now slowly pull back on the plunger until the correct dose of GM-CSF is in the syringe. • Before withdrawing the needle from the rubber stopper, be sure there are no air bubbles in the syringe. The air bubbles are harmless but they can decrease the amount of GM-CSF you receive. If there are air bubbles, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. To remove air bubbles, gently push some of the solution back into the vial. Now slowly pull back on the plunger until the correct dose of GM- CSF is in the syringe. Repeat this procedure as needed until you can draw up the correct dose of GM-CSF without air bubbles. • Withdraw the needle from the rubber stopper. Do not lay down the syringe or allow the needle to touch anything.
Inject the GM-CSF • With one hand, gently smooth the skin of the injection site (the area you wiped with the alcohol swab) between your thumb and forefinger so it is taut. • With your other hand, hold the syringe, just like a pencil, at a 90 degree angle to the skin, about 2 inches above the surface of the skin. Using a quick, short motion, insert the needle. • Release your grasp on the skin. Gently pull back on the plunger just a little bit (about 1/8 of an inch). If you do not see blood in the syringe, slowly inject all of the GM-CSF by pushing the plunger all the way down. If you see blood in the syringe, do not inject GM-CSF. Withdraw the needle at the same angle it was inserted. Finding blood in the syringe simply means you hit a blood vessel rather than the fatty tissues you need to inject into, and is not a cause for concern. Discard the syringe in a puncture-resistant container. Repeat the steps to prepare a new syringe.
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Choose, clean, and ice a new injection site. Remember to check again for blood before injecting GM-CSF. • Remove the needle at the same angle as it was inserted. • Lightly touch an alcohol swab over the injection site until any bleeding has stopped. Do not rub or press the site because doing so may irritate the area. Dispose of Supplies • It is extremely important that you do not reuse syringes or needles. Do not attempt to put the needle cover back on the needle. Throw away used syringes and needles in a puncture-resistant container as instructed by your doctor, nurse, or pharmacist. They may be able to supply you with a container made specifically for disposing of used syringes and needles. If not, then you may use the following: A hard plastic container that you cannot see through with a screw-on cap, such as an empty bleach or laundry detergent bottle. Always screw the cap on tightly after disposing of your syringes and needles. Do not recycle the container. A metal container with a plastic lid, such as a coffee can. Cut a hole in the plastic lid and tape the lid to the metal container. DO NOT use a glass or clear plastic container, or any container that will be recycled or returned to a store. • Keep the container out of the reach of children. Make sure the container is properly labeled as to its content. • When the container is about two-thirds (2/3) full, dispose of it as instructed. There may be special state and local laws regarding the proper disposal of needles and syringes that your doctor, nurse, or pharmacist may discuss with you.
Rev. 4/11 • Throw away used alcohol swabs in the trash. Rev. 4/11 • Unused, partially used, expired or empty containers of GM-CSF should be returned to the hospital for proper destruction. Rev. 4/11 • GM-CSF older than 20 days should be returned to the hospital for proper destruction.
IMPORTANT NOTES • Follow the instructions given to you by your doctor, nurse, or pharmacist. Do not make any changes in your dose or how often you give yourself GM-CSF. If you are not sure about the amount (mL or cc) or dose to be used, talk to your doctor, nurse, or pharmacist. • Try to get into a routine; give yourself GM-CSF at the same time each day. • Keep GM-CSF and all supplies out of the reach of children. • If any of the following happens to you, contact your doctor, nurse, or pharmacist: You miss a dose of GM-CSF. You notice anything unusual about your condition while you are taking GM-CSF. You develop a high fever (over 100.5° F or 38° C). You notice any signs of infection, including chills, sore throat, or congestion (such as a stuffy nose).
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A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma
Rev. 4/11, 4/12 Appendix XV Pre-Existing Autoimmune Diseases
Patients with a known history of the following autoimmune related diseases are not eligible to participate in this trial:
Acute disseminated encephalomyelitis Addison's disease Alopecia universalis Ankylosing spondylitis Antiphospholipid antibody syndrome Aplastic anemia Asthma Autoimmune hemolytic anemia Autoimmune hepatitis Autoimmune hypoparathyroidism Autoimmune hypophysitis Autoimmune myocarditis Autoimmune oophoritis Autoimmune orchitis Autoimmune thrombocytopenic purpura Behcet's disease Bullous pemphigold Celiac disease Chronic fatigue syndrome Chronic inflammatory demyelinating polyneuropathy Churg-Strauss syndrome Crohn's disease Dermatomyositis Dysautonomia Eczema Epidermolysis bullosa acquista Gestational pemphigoid Giant cell arteritis Goodpasture's syndrome Graves' disease Guillain-Barré syndrome Hashimoto's disease IgA nephropathy Inflammatory bowel disease Interstitial cystitis Kawasaki's disease Lambert-Eaton myasthenia syndrome Lupus erythematosus Lyme disease - chronic Meniere's syndrome Mooren's ulcer Morphea Multiple sclerosis Myasthenia gravis Neuromyotonia Opsoclonus myoclonus syndrome
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Optic neuritis Ord's thyroiditis Pemphigus Pernicious anemia Polyarteritis nodusa Polyarthritis Polygrandular autoimmune syndrome Primary biliary cirrhosis Psoriasis Reiter's syndrome Rheumatoid arthritis Sarcoidosis Scleroderma Sjögren's syndrome Stiff-Person syndrome Takayasu's arteritis Ulcerative colitis Vogt-Kovanagi-Harada disease Vulvodynia Wegener's granulomatosis
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